EP0532456A1 - 1-Acylpiperidine derivatives and their use as substance P antagonists - Google Patents

Abstract

1-Acylpiperidine compound of the formula I <IMAGE> (I) in which R1 is an optionally substituted aralkyl, aryloxyalkyl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl radical or the acyl radical of an alpha -amino acid which is optionally N-substituted by lower alkanoyl or carbamoyl-lower-alkanoyl, R2 is cycloalkyl or an optionally substituted aryl or heteroaryl radical, R3 is hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl radical which is optionally substituted by carboxyl or esterified or amidated carboxyl, R4 is an optionally substituted aryl or optionally partially hydrogenated heteroaryl radical, X1 is methylene, ethylene, a direct linkage, an optionally ketalised carbonyl group or an optionally etherified hydroxymethylene group, X2 is alkylene, carbonyl or a direct linkage, and X3 is carbonyl, oxo-lower-alkylene, oxo(aza)-lower-alkylene or an alkylene radical which is optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxyl or, in higher than the alpha position, by hydroxyl, and its salts have substance-P-antagonistic properties and can be used as pharmaceutically active substances in pharmaceuticals for the treatment of disorders in whose development substance P plays an essential part.

Description

worin R₁ einen gegebenenfalls substituierten Aralkyl-, Aryloxyalkyl-, Heteroaralkyl-, Aroyl-, Heteroaroyl-, Cycloalkylcarbonyl-, Aralkanoyl-, Heteroarylalkanoyl-, Aralkoxycarbonyl- oder Arylcarbamoylrest oder den Acylrest einer gegebenenfalls durch Niederalkanoyl oder Carbamoylniederalkanoyl N-substituierten α-Aminosäure bedeutet, R₂ Cycloalkyl oder einen gegebenenfalls substituierten Aryl- oder Heteroarylrest darstellt, R₃ für Wasserstoff, Alkyl, Carbamoyl oder einen gegebenenfalls durch Carboxy oder verestertes oder amidiertes Carboxy substituierten Alkanoyl- oder Alkenoylrest steht, R₄ einen gegebenenfalls substituierten Aryl- oder gegebenenfalls partiell hydrierten Heteroarylrest bedeutet, X₁ Methylen, Ethylen, eine direkte Bindung, eine gegebenenfalls ketalisierte Carbonylgruppe oder eine gegebenenfalls veretherte Hydroxymethylengruppe darstellt, X₂ für Alkylen, Carbonyl oder eine direkte Bindung steht und X₃ Carbonyl, Oxoniederalkylen, Oxo(aza)niederalkylen oder einen gegebenenfalls durch Phenyl, Hydroxymethyl, gegebenenfalls verestertes oder amidiertes Carboxy oder in höherer als der α-Stellung durch Hydroxy substituierten Alkylenrest darstellt, und ihre Salze, Verfahren zur Herstellung der erfindungsgemässen Verbindungen, diese enthaltende pharmazeutische Präparate und ihre Verwendung als Arzneimittelwirkstoffe.The invention relates to new 1-acylpiperidine compounds of the formula I.

wherein R₁ represents an optionally substituted aralkyl, aryloxyalkyl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl radical or the acyl radical of an optionally substituted by lower alkanoyl or carbamoyl lower amino, R₂ represents cycloalkyl or an optionally substituted aryl or heteroaryl radical, R₃ represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl radical optionally substituted by carboxy or esterified or amidated carboxy, R₄ represents an optionally substituted aryl or optionally partially hydrogenated heteroaryl radical, X₁ Methylene, ethylene, a direct bond, an optionally ketalized carbonyl group or an optionally etherified hydroxymethylene group, X₂ represents alkylene, carbonyl or a direct bond and X₃ carbonyl, oxo lower alkylene, oxo (aza) lower alkylene or represents an optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxy or in higher than the α-position by hydroxy alkylene radical, and their salts, processes for the preparation of the compounds according to the invention, pharmaceutical preparations containing them and their use as active pharmaceutical ingredients.

The aryl, aroyl, aralkanoyl, heteroaryl and heteroaroyl radicals mentioned can be unsubstituted or substituted, for example by aromatically bound lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, such as mono-, di- or tri-substituted, in particular mono- or disubstituted . Aryl, aralkyl, aryloxyalkyl, cycloalkylcarbonyl and aroyl radicals are preferably in the stated Manner mono- or disubstituted, such as 3-mono- or 3,5-disubstituted; Heteroaryl, heteroaralkyl, heteroaralkanoyl and heteroaroyl radicals are preferably unsubstituted. Aralkyl is, for example, optionally substituted phenyl or diphenyl-lower alkyl in the phenyl or naphthyl part.

Aryloxy lower alkyl is, for example, optionally substituted phenoxy lower alkyl in the phenyl part.

Heteroaralkyl is, for example, a 6-membered monocyclic heteroaryl radical or a bicyclic azaheteroaryl comprising alkyl having a 6-membered and a 5- or 6-membered ring.

Aroyl is, for example, optionally substituted benzoyl, such as benzoyl, 3-lower alkyl, 3-lower alkoxy, 3-halogeno, 3-dimethylamino, 3,5-di-lower alkyl, 3,5-di-lower alkoxy, 3,5-dihalo or 3,5-ditrifluoromethylbenzoyl, or secondarily optionally substituted naphthoyl, such as 1- or 2-naphthoyl.

Heteroaroyl is, for example, 6-membered monocyclic or bicyclic azaheteroaroyl composed of a 6-membered and a 5- or 6-membered ring, such as pyridylcarbonyl or quinolinylcarbonyl.

Cyloalkanoyl is, for example, optionally substituted 3- to 8-, in particular 5- to 7-membered, cycloalkylcarbonyl, such as cyclohexylcarbonyl, 3-lower alkyl, 3-lower alkoxy, 3-halogeno, 3-dimethylamino, 3,5-di-lower alkyl, 3,5-di-lower alkoxy, 3,5-dihalo or 3,5-ditrifluoromethylcyclohexylcarbonyl.

Aralkanoyl means, for example, optionally substituted phenyl- or diphenyl-lower alkanoyl in the phenyl part.

Heteroarylalkanoyl is, for example, a 6-membered monocyclic heteroaryl radical or a bicyclic azaheteroaryl heteroaryl-lower alkanoyl composed of a 6-membered and a 5- or 6-membered ring.

Arylcarbamoyl means, for example, N-phenylcarbamoyl which is unsubstituted or optionally substituted in the phenyl part.

worin R₅ Wasserstoff, oder einen gegebenenfalls durch Hydroxy, Amino, Mercapto, gegebenenfalls durch Hydroxy substituiertes Phenyl, Carboxy, Carbamoyl oder Ureido substituiertes Niederalkyl-, wie C₁-C₄-Alkylrest, z.B. Methyl, Isopropyl, Isobutyl, Sekundärbutyl, Hydroxymethyl, Mercaptomethyl, 2-Methylmercaptoethyl, 3-Ureidopropyl, 4-Aminobutyl, Carboxymethyl, Carbamoylmethyl, 2-Carboxyethyl, 2-Carbamoylethyl, Benzyl oder 4-Hydroxybenzyl, und R₆ Niederalkanoyl, beispielsweise C₂-C₇-Alkanyol, wie Acetyl, Propionyl, Butyryl oder Pivaloyl, bedeutet. Es kann sich aber auch um die Acylgruppe einer heterocyclischen, als Peptidbaustein natürlich vorkommenden α-Aminosäure, wie Prolyl, Tryptophanyl oder Histidinyl, handeln.Acyl residues of optionally N-alkanoylated α-amino acids are derived in particular from naturally occurring as peptide building blocks, optionally lower alkanoylated, for example N-C₂-C₇-alkanoylated, such as substituted by acetyl, propionyl, butyryl or pivaloyl, α-amino acids. For example, there are groups of the formula

wherein R₅ is hydrogen, or a lower alkyl, such as C₁-C₄ alkyl, e.g. methyl, isopropyl, isobutyl, secondary butyl, hydroxymethyl, mercaptomethyl, optionally substituted by hydroxy, amino, mercapto, optionally substituted by hydroxyl, carboxy, carbamoyl or ureido, 2nd -Methylmercaptoethyl, 3-ureidopropyl, 4-aminobutyl, carboxymethyl, carbamoylmethyl, 2-carboxyethyl, 2-carbamoylethyl, benzyl or 4-hydroxybenzyl, and R₆ lower alkanoyl, for example C₂-C₇-alkanyol, such as acetyl, propionyl, butyryl or pivaloyl . However, it can also be the acyl group of a heterocyclic α-amino acid naturally occurring as a peptide building block, such as prolyl, tryptophanyl or histidinyl.

Cycloalkyl is, for example, 5- to 7-membered cycloalkyl, such as in particular cyclohexyl or secondarily cyclopentyl or cycloheptyl.

Aryl is, for example, phenyl or, in particular as R₄, naphthyl.

Heteroaryl is, for example, 6-membered monocyclic azaheteroaryl, such as pyridyl, or, as R₄, in particular a heteroaryl, such as benzofuranyl, such as benzofuranyl, e.g. Benzofuran-2-yl or -3-yl, indolyl, e.g. Indol-2-yl or -3-yl, 2,3-dihydroindolyl, e.g. 2,3-dihydroindol-2-yl or -3-yl, benzimidazolyl, e.g. Benzimidazol-2-yl, quinolyl, e.g. Quinolin-4-yl, or 1,2,3,4-tetrahydroquinolin-4-yl.

Heteroaryl-lower alkanoyl, for example corresponding heteroaryl-C₁-C₄-alkanoyl, such as 2-pyridyl- or 4-pyridylacetyl, is a heteroaryl radical having 6-membered monocyclic or a bicyclic azaheteroaryl composed of a 6-membered and a 5- or 6-membered ring and a 5- or 6-membered ring , 4,9-tetrahydro-1H-pyrido [3,4-b] indol-3-ylcarbonyl.

Alkyl is especially lower alkyl; Alkylene, especially lower alkylene.

Ketalized carbonyl groups are, for example, ketalized with an aliphatic alcohol or dialcohol, such as with a lower alkanol or a lower alkanediol, and mean, for example, di-lower alkoxymethylene or lower alkylenedioxymethylene.

Etherified hydroxymethylene is etherified in particular with an aliphatic alcohol, such as a lower alkanol, and means, for example, lower alkoxymethylene.

Optionally esterified or amidated carboxy is, for example, carboxy, lower alkoxycarbonyl, carbamoyl or N-mono- or N, N-di-lower alkylcarbamoyl.

Alkanoyl or alkenoyl radicals optionally substituted by carboxy or esterified or amidated carboxy are, for example, lower alkanoyl, such as C₂-C₇-alkanoyl, such as acetyl, propionyl, butyryl or pivaloyl, carboxy-lower alkanoyl, such as carboxy-C₃-C₇-alkanoyl, or succinoyl, such as succinoyl , or carboxy lower alkenoyl, such as carboxy-C₃-C₅-alkenoyl, such as maleyl, fumaroyl or tartroyl, in which carboxy can also be esterified or amidated and for example lower alkoxycarbonyl, such as C₁-C₄-alkoxycarbonyl, for example Methoxy or ethoxycarbonyl, carbamoyl or N-mono- or N, N-di-lower alkylcarbamoyl such as N-mono- or N, N-di-C₁-C₄-alkylcarbamoyl, e.g. N-methyl or N, N-dimethylcarbamoyl.

Lower alkylene substituted at higher positions than the α-position by hydroxyl is, for example, hydroxylated in the 2-position to the N atom.

Lower alkylene substituted by hydroxymethyl or optionally esterified or amidated carboxy is substituted, for example, in the 1-, 2- or, if present, 3-position to the N atom by carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N, N-di-lower alkylcarbamoyl or hydroxymethyl .

Above and below, lower radicals and compounds are understood to mean, for example, those which have up to and with 7, preferably up to and with 4, carbon atoms (C atoms).

Lower alkyl is, for example, C₁-C₇-alkyl, preferably C₁-C₄-alkyl, such as in particular Methyl or secondarily ethyl, propyl, isopropyl or butyl, but can also be isobutyl, secondary butyl, tertiary butyl or a Cs-Cr-alkyl group, such as pentyl, hexyl or heptyl.

Lower alkylene is, for example, C₁-C₇ alkylene, preferably C₁-C₄ alkylene such as methylene, ethylene, 1,3-propylene, 1,4-butylene or 1,5-pentylene.

Phenyl- or diphenyl-lower alkyl optionally substituted in phenyl is, for example, corresponding phenyl or diphenyl-C₁-C₄-alkyl, such as benzyl, 2,4-dichlorobenzyl, 3,5-ditrifluoromethylbenzyl, 2-phenylethyl or 2,2-diphenylethyl.

In the phenyl part optionally substituted phenyl or diphenyl-lower alkanoyl is, for example, corresponding phenyl or diphenyl-C₁-C₄-alkanoyl, such as 2,2-diphenylacetyl or 2,3-diphenylpropionyl.

Phenoxy-lower alkyl optionally substituted in phenyl is, for example, phenoxy-C₁-C₄-alkyl substituted by halogen and / or triazolyl, such as 2- [2- (1H-1,2,4-triazol-1-yl) -4-chlorophenoxy] ethyl.

Heteroaryl-lower alkyl having 6-membered monocyclic heteroaryl radical or bicyclic azaheteroaryl composed of a 6-membered and a 5- or 6-membered ring. is, for example, pyridyl or quinolinyl-C₁-C₄-alkyl, such as 4-quinolinylmethyl.

Lower alkoxy is, for example, C₁-C₇-alkoxy, preferably C₁-C₄-alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy, but can also be isobutyloxy, secondary butyloxy, tertiary butyloxy or a pentyloxy, hexyloxy or heptyloxy group.

Halogen is, for example, halogen of atomic number up to and including 35, such as chlorine or fluorine, and also bromine.

Lower alkoxycarbonyl is, for example, C₁-C₇-alkoxycarbonyl, preferably C₁-C₄-alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl or butyloxycarbonyl, but can also be isobutyloxycarbonyl, secondary butyloxycarbonyl, tertiary butyloxycarbonyl or a pentyloxycarbonyl Be hexyloxycarbonyl or heptyloxycarbonyl group.

N-Lower alkylcarbamoyl is, for example, N-C₁-C₇-alkylcarbamoyl, preferably N-C₁-C₄-alkylcarbamoyl, such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl or butylcarbamoyl, but also isobutylcarbamoyl, secondary butyl carbamoylamylbutylcarbamoylamyl, carbamoylamylbutylcarbamoyl, carbamoylamyl, carbamoyl, carbamoyl or carbamoylamylbutylcarbamoyl, be.

N, N-diniederalkylcarbamoyl is, for example, N, N-di-C₁-C₇-alkylcarbamoyl, preferably N, N-di-C₁-C₄-alkylcarbamoyl, such as N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-ethyl-N -methyl-carbamoyl, N, N-dipropylcarbamoyl, N-methyl-N-propyl-carbamoyl, N-isopropyl-N-methyl-carbamoyl or N-butyl-N-methyl-carbamoyl, but can also be N-isobutyl-N- methyl-carbamoyl, N-methyl-N-secondary-butyl-carbamoyl, N-methyl-N-tert-butyl-carbamoyl or an N-methyl-N-pentyl-carbamoyl-, N-hexyl-N-methyl-carbamoyl or N-heptyl -N-methyl-carbamoyl group.

Lower alkylene substituted by hydroxy in a position higher than the α position and lower than the ω position is, for example, 1,3- (2-hydroxy) propylene, 1,4- (2-hydroxy) butylene, 1,4- (3- Hydroxy) butylene, 1,5- (2-hydroxy) pentylene, 1,5- (3-hydroxy) pentylene or 1,5- (4-hydroxy) pentylene.

Lower alkylene substituted by carboxy is, for example, carboxymethylene, 1- or 2-carboxyethylene, 1,3- (2-carboxy) propylene, 1,4- (2-carboxy) butylene, 1,4- (3-carboxy) butylene, 1, 5- (2-carboxy) pentylene, 1,5- (3-carboxy) pentylene or 1,5- (4-carboxy) pentylene.

Lower alkylene substituted by lower alkoxycarbonyl is, for example, lower alkoxycarbonylmethylene, 1- or 2-lower alkoxycarbonylethylene, 1,3- (2-lower alkoxycarbonyl) propylene, 1,4- (2-lower alkoxycarbonyl) butylene, 1,4- (3-lower alkoxycarbonyl) butylene, 1, 5- (2-lower alkoxycarbonyl) pentylene, 1,5- (3-lower alkoxycarbonyl) pentylene or 1,5- (4-lower alkoxycarbonyl) pentylene, lower alkoxycarbonyl in each case, for example, C₁-C₄alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl, means.

Substituted by carbamoyl, N-mono- or N, N-di-lower alkylcarbamoyl Lower alkylene is particularly substituted by carbamoyl and means, for example, carbamoylmethylene, 1- or 2-carbamoylethylene, 1,3- (2-carbamoyl) propylene, 1,4- (2-carbamoyl) butylene, 1,4- (3-carbamoyl) butylene , 1,5- (2-carbamoyl) pentylene, 1,5- (3-carbamoyl) pentylene or 1,5- (4-carbamoyl) pentylene.

Lower alkylene substituted by hydroxymethyl is, for example, 2-hydroxyethylidene, 2,3- (1-hydroxy) propylene, 1,3- (2-hydroxymethyl) propylene, 2,4- (1-hydroxy) butylene, 1,4- (2- Hydroxymethyl) butylene, 1,4- (3-hydroxymethyl) butylene, 1,5- (2-hydroxymethyl) pentylene, 1,5- (3-hydroxymethyl) pentylene or 1,5- (4-hydroxymethyl) pentylene.

Lower alkoxymethylene is, for example, C₁-C₄ alkoxymethylene, such as methoxymethylene, ethoxymethylene, propyloxymethylene or butyloxymethylene.

Diniederalkoxymethylene is for example di-C₁-C₄ alkoxymethylene, such as dimethoxymethylene, diethoxymethylene, dipropyloxymethylene or dibutyloxymethylene.

Lower alkylenedioxymethylene is, for example, 5- to 8-membered, in particular 5- or 6-membered 1,3-dioxacycloalk-2-yl, such as 1,3-dioxacyclobut-2-yl, 1,3-dioxacyclopent-2-yl (1, 3-dioxolan-2-yl), 1,3-dioxacyclohex-2-yl (1,3-dioxan-2-yl) or 1,3-dioxacyclohept-2-yl.

The compounds of formula I have basic or, if R₃ and / or X₃ is substituted by carboxy, amphoteric in character and can accordingly form acid addition salts and optionally internal salts.

Acid addition salts of compounds of formula I are, for example, their pharmaceutically usable salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, e.g. Hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, e.g. methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfaminates (cyclamates).

For isolation or purification, pharmaceutically unsuitable salts can also be used. Only pharmaceuticals are used therapeutically usable, non-toxic salts, which are therefore preferred.

The compounds provided according to the invention have valuable pharmacological properties. In particular, they show a pronounced antagonistic action against substance P and have the range of properties typical of substance P antagonists. Thus, the compounds of formula I and their pharmaceutically usable salts in vitro bind the ³H substance-P to the bovine retina in the radioreceptor assay according to H. Bittiger, Ciba Foundation Symposium 91 , 196-199 (1982) in concentrations completely inhibited from about 10 µmol / L. In vivo , from a dose of about 0.01 mg / kg iv, they inhibit the vasodilation on the guinea pig ear caused by substance P, measured in accordance with the experimental set-up by Andrews and Helmets, Regul. Pept. 25 , 267-275 (1989) and from a dose of about 1.0 mg / kg iv based on the experimental setup by Lundberg et al, Proc. Nat. Acad. Sci. (USA) 80 , 1120-1124 vagally induced bronchospasms of guinea pigs, which indicates their suitability for the treatment of asthma. Their usefulness for the treatment of diseases of the central nervous system results, for example, from their inhibitory effect on behavioral changes of gerbils (gerbil) induced by icv- applied substance P-methyl ester according to A. Vassout et al., Meeting on Substance P, Worcester, Mass ( 1990) with an ED₅₀ from about 10 mg / kg sc, from about 30 mg / kg ip and from about 100 mg / kg po

Substance P is a naturally occurring undecapeptide of the tachykinin family. It is produced in a mammalian organism and acts pharmacologically as a neuropeptide. Substance P plays an essential role in various diseases, for example pain, migraines and some disorders of the central nervous system, such as anxiety, schizophrenia and depression, as well as certain motor disorders, such as Parkinson's disease, but also inflammatory diseases such as rheumatoid Arthritis, iritis and conjunctivitis, in diseases of the respiratory system, such as in asthma and chronic bronchitis, in diseases of the gastrointestinal system, such as in ulcerative colitis and Crohn's disease, and in hypertension.

There has been no shortage of attempts to develop substance P antagonists. However, a number of the substance P antagonists known to date are peptide compounds which are metabolically too labile to be used as active pharmaceutical ingredients.

In contrast, the substance P antagonists of the formula I and their pharmaceutically usable salts are metabolically stable and are therefore particularly suitable for the therapeutic treatment of the diseases mentioned.

The invention relates primarily to compounds of formula I, wherein R₁ is an unsubstituted or in the phenyl part by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and / or trifluoromethyl substituted phenyl, diphenyl, naphthyl or fluorenyl-lower alkyl radical, an unsubstituted or in the phenyl part by halogen and / or triazolyl-substituted phenoxy-lower alkyl radical, a 6-membered monocyclic heteroaryl radical or a bicyclic azaheteroaryl bicyclic azaheteroaryl composed of a 6-membered and a 5- or 6-membered ring, a heteroaryl-lower alkyl group, an unsubstituted or by lower alkyl, lower alkoxy and hydroxy, hydroxy, di-lower alkylamino / or trifluoromethyl-substituted benzoyl, naphthoyl, fluorenoyl or 3- to 8-membered cycloalkylcarbonyl, an unsubstituted or in the phenyl part by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and / or trifluoromethyl-substituted phenyl or diphenyl-lower alkanoyl radical, a bi- or tricyclic azaheteroaryl having 6-membered monocyclic or a 6-membered and one or two 5- or 6-membered ring (s) containing heteroaryl-lower alkanoyl residue, an unsubstituted or in the phenyl part by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and halogen / or trifluoromethyl-substituted phenyl-lower alkoxycarbonyl or N-phenylcarbamoyl radical or the acyl radical of an α-amino acid which is optionally substituted by lower alkanoyl or carbamoyl-lower alkanoyl and which occurs naturally as a peptide building block, R₂ denotes 5- to 7-membered cycloalkyl or an unsubstituted or substituted by aromatic Represents lower alkoxy, halogen and / or trifluoromethyl substituted phenyl, naphthyl or 6-membered monocyclic azaheteroaryl radical, R₃ for hydrogen, lower alkyl, carbamoyl, lower alkanoyl, carboxy-lower alkanoyl or carboxy-lower alkenoyl, lower alkoxycarbonyl-lower alkyl, carb amoyl-lower alkanoyl, N-mono- or N, N-di-lower alkylcarbamoyl-lower alkanoyl, N-cycloalkylcarbamoyl-lower alkanoyl or N-phenylcarbamoyl-lower alkanoyl, R₄ is an unsubstituted or unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl or phenyl or phenyl or pyryl or pyridyl or pyridyl or pyridyl or pyridyl or pyridyl or phenyl or pyridyl or pyrid substituted or unsubstituted phenyl or pyridyl or pyridyl or phenyl or pyridyl or substituted phenyl, or a phenyl or pyrid substituted or unsubstituted phenyl or pyridyl or phenyl or pyridyl or substituted phenyl or phenyl or phenyl or pyridyl or n-substituted phenyl or a phenyl or pyridyl substituted or unsubstituted phenyl or pyridyl or substituted or by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl C-substituted and optionally by lower alkanoyl N-substituted, from an optionally partially hydrogenated 5- or 6-membered mono- or diaza or oxaheteroaryl residue and a 6-membered aryl residue heteroaryl residue, X 1 is methylene, ethylene, a carbonyl group optionally ketalized with a lower alkanol or a lower alkanediol, represents an optionally etherified with a lower alkanol hydroxymethylene group or a direct bond, X₂ is carbonyl, lower alkylene or a direct bond and X₃ carbonyl, oxo lower alkylene, oxo (aza) lower alkylene or an unsubstituted or by phenyl or in 1-, 2- or, if present, 3-position to the N atom by carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N, N-N-lower alkylcarbamoyl or hydroxymethyl substituted lower alkylene radical, and their salts.

darstellt, in der R₅ Wasserstoff, unsubstituiertes oder durch Hydroxy, Mercapto, Amino, gegebenenfalls durch Hydroxy substituiertes Phenyl, Carboxy, Carbamoyl oder Ureido substituiertes C₁-C₄-Alkyl und R₆ C₂-C₇-Alkanoyl bedeutet, R₂ 5- bis 7-gliedriges Cycloalkyl oder einen unsubstituierten oder durch C₁-C₄-Alkyl, C₁-C₄-Alkoxy, Halogen und/oder Trifluormethyl substituierten Phenyl-, Naphthyl- oder Pyridylrest darstellt, R₃ für Wasserstoff, C₁-C₇-Alkyl, Carbamoyl, C₂-C₇-Alkanoyl, Carboxy-C₁-C₄-alkanoyl oder Carboxy-C₂-C₄-alkenoyl steht, R₄ unsubstituiertes oder durch C₁-C₄-Alkyl, C₁-C₄-Alkoxy, Halogen und/oder Trifluormethyl substituiertes Phenyl oder Naphthyl oder unsubstituiertes Pyridyl, Benzofuranyl, Indolyl, 2,3-Dihydroindolyl, Benzimidazolyl, Chinolyl oder 1,2,3,4-Tetrahydrochinolinyl bedeutet, X₁ Methylen, Hydroxymethylen, C₁-C₄-Alkoxymethylen, Carbonyl oder Di-C₁-C₄-alkoxymethylen oder eine direkte Bindung darstellt, X₂ für C₁-C₇-Alkylen, Carbonyl oder eine direkte Bindung steht und X₃ Carbonyl, C₁-C₄-Alkylen, Carboxy-C₁-C₄-alkylen, C₁-C₄-Alkoxycarbonyl-C₁-C₄-alkylen, Carbamoyl-C₁-C₄-alkylen oder Hydroxymethyl-C₁-C₄-alkylen darstellt, und ihre Salze.The invention relates in particular to compounds of the formula I in which R₁ is phenyl- or diphenyl-C₁-C₄-alkyl, such as benzyl, 2,4-dichlorobenzyl, 3 which is unsubstituted or substituted in the phenyl part by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and / or trifluoromethyl , 5-ditrifluoromethylbenzyl, 2-phenylethyl or 2,2-diphenylethyl, unsubstituted or substituted in the phenyl by halogen and / or triazolyl phenoxy-C₁-C₄-alkyl, pyridyl- or quinolinyl-C₁-C₄-alkyl, such as 4-quinolinylmethyl, unsubstituted or substituted by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and / or trifluoromethyl, such as benzoyl, 3-lower alkyl, 3-lower alkoxy, 3-halogen, 3-dimethylamino, 3,5-di-lower alkyl, 3,5 -Di-lower alkoxy-, 3,5-dihalo- or 3,5-ditrifluoromethylbenzoyl, or secondarily unsubstituted or substituted by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and / or trifluoromethyl naphthoyl, such as 1- or 2-naphthoyl, unsubstituted pyridylcarbonyl or quinolinylcarbonyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl or 5-to 7-membered cycloalkylcarbonyl, such as cyclohexylcarbonyl, 3-methyl-, 3-methoxy, substituted by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and / or trifluoromethyl -, 3-chloro, 3-dimethylamino, 3,5-dimethyl, 3,5-dimethoxy, 3,5-dichloro- or 3,5-ditrifluoromethylcyclohexylcarbonyl, unsubstituted or in phenyl by lower alkyl, lower alkoxy, di-lower alkylamino, Halogen and / or trifluoromethyl-substituted phenyl- or diphenyl-C₁-C₄-alkanoyl, such as 2,2-diphenylacetyl or 2,3-diphenylpropionyl, unsubstituted or substituted in the phenyl part optionally by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and / or trifluoromethyl Phenylcarbamoyl or a group of formula Ia

represents in the R₅ is hydrogen, unsubstituted or substituted by hydroxy, mercapto, amino, optionally substituted by hydroxyl, carboxy, carbamoyl or ureido substituted C₁-C₄-alkyl and R₆ C₂-C₇-alkanoyl, R₂ is 5- to 7-membered cycloalkyl or represents an unsubstituted or substituted by C₁-Crest-alkyl, C₁-C₄-alkoxy, halogen and / or trifluoromethyl phenyl, naphthyl or pyridyl radical, R₃ represents hydrogen, C₁-C₇-alkyl, carbamoyl, C₂-C₇-alkanoyl, Carboxy-C₁-C₄-alkanoyl or carboxy-C₂-C₄-alkenoyl, R₄ is unsubstituted or substituted by C₁-C₄-alkyl, C₁-C₄-alkoxy, halogen and / or trifluoromethyl-phenyl or naphthyl or unsubstituted pyridyl, benzofuranyl, indolyl, 2,3-dihydroindolyl, benzimidazolyl, quinolyl or 1,2,3,4-tetrahydroquinolinyl means X₁ is methylene, hydroxymethylene, C₁-C₄-alkoxymethylene, carbonyl or di-C₁-C₄-alkoxymethylene or a direct bond, X ₂ represents C₁-C₇-alkylene, carbonyl or a direct bond and X₃ carbonyl, C₁-C₄-alkylene, carboxy-C₁-C₄-alkylene, C₁-C₄-alkoxycarbonyl-C₁-C₄-alkylene, carbamoyl-C₁-C₄- represents alkylene or hydroxymethyl-C₁-C₄-alkylene, and their salts.

darstellt, in der R₅ Wasserstoff, unsubstituiertes oder durch Hydroxy, Mercapto, Amino, gegebenenfalls durch Hydroxy substituiertes Phenyl, Carboxy, Carbamoyl oder Ureido substituiertes C₁-C₄-Alkyl, beispielsweise Methyl, Isopropyl, Isobutyl, Sekundärbutyl, Hydroxymethyl, Mercaptomethyl, 2-Methylmercaptoethyl, 3-Ureidopropyl, 4-Aminobutyl, Carboxymethyl, Carbamoylmethyl, 2-Carboxyethyl, 2-Carbamoylethyl, Benzyl oder 4-Hydroxybenzyl, und R₆ C₂-C₇-Alkanoyl, wie Acetyl, Propionyl, Butyryl oder Pivaloyl, bedeutet, R₂ 5- bis 7-gliedriges Cycloalkyl, insbesondere Cyclohexyl oder in zweiter Linie Cyclopentyl oder Cycloheptyl, oder einen unsubstituierten oder durch C₁-C₄-Alkyl, wie Methyl, C₁-C₄-Alkoxy, wie Methoxy, Halogen und/oder Trifluormethyl substituierten Phenyl-, Naphthyl- oder Pyridylrest darstellt, R₃ für Wasserstoff, C₁-C₇-Alkyl, wie Methyl, Ethyl, Propyl, Isopropyl oder Butyl, Isobutyl, Sekundärbutyl oder Tertiärbutyl, Carbamoyl, C₂-C₇-Alkanoyl, wie Acetyl, Propionyl, Butyryl oder Pivaloyl, Carboxy-C₁-C₄-alkanoyl, wie Succinoyl, Glutaroyl oder Adipoyl, oder Carboxy-C₃-C₅-alkenoyl, wie Maleyl, Fumaroyl oder Tartroyl, steht, R₄ unsubstituiertes oder durch C₁-C₄-Alkyl, wie Methyl, C₁-C₄-Alkoxy, wie Methoxy, Halogen und/oder Trifluormethyl substituiertes Phenyl oder Naphthyl oder unsubstituiertes Pyridyl, Benzofuranyl, Indolyl, Benzimidazolyl oder Chinolyl bedeutet, X₁ Methylen, Hydroxymethylen, C₁-C₄-Alkoxymethylen, wie Methoxymethylen, Ethoxymethylen, Propyloxymethylen oder Butyloxymethylen, Carbonyl, Di-C₁-C₄-alkoxymethylen, wie Dimethoxymethylen, Diethoxymethylen, Dipropyloxymethylen oder Dibutyloxymethylen, oder eine direkte Bindung darstellt, X₂ für C₁-C₇-Alkylen, wie Methylen oder in zweiter Linie Ethylen oder 1,3-Propylen, Carbonyl oder eine direkte Bindung steht und X₃ Carbonyl, C₁-C₄-Alkylen, wie Methylen, Ethylen oder 1,3-Propylen, Carboxy-C₁-C₄-alkylen, wie 1,3-(2-Carboxy)propylen, 1,4-(2-Carboxy)butylen, 1,4-(3-Carboxy)butylen, C₁-C₄-Alkoxycarbonyl-C₁-C₄-alkylen, wie 1,3-(2-C₁-C₄-Alkoxycarbonyl)propylen, 1,4-(2-C₁-C₄-Alkoxycarbonyl)butylen, 1,4-(3-C₁-C₄-Alkoxycarbonyl)butylen, 1,5-(2-C₁-C₄-Alkoxycarbonyl)pentylen, 1,5-(3-C₁-C₄-Alkoxycarbonyl)pentylen oder 1,5-(4-C₁-C₄-Alkoxycarbonyl)pentylen, wobei C₁-C₄-Alkoxycarbonyl jeweils beispielsweise Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl oder Butoxycarbonyl, bedeutet, Carbamoyl-C₁-C₄-alkylen, wie 1,3-(2-Carbamoyl)propylen, 1,4-(2-Carbamoyl)butylen, 1,4-(3-Carbamoyl)butylen, 1,5-(2-Carbamoyl)pentylen, 1,5- (3-Carbamoyl)pentylen oder 1,5-(4-Carbamoyl)pentylen, oder Hydroxymethyl-C₁-C₄-alkylen, wie 1,3-(2-Hydroxymethyl)propylen, 1,4-(2-Hydroxymethyl)butylen, 1,4-(3-Hydroxymethyl)butylen, 1,5-(2-Hydroxymethyl)pentylen, 1,5-(3-Hydroxymethyl)pentylen oder 1,5-(4-Hydroxymethyl)pentylen, darstellt, und ihre Salze.The invention particularly relates to compounds of the formula I in which R₁ is unsubstituted or substituted by C₁-C₄-alkyl, such as methyl, C₁-C₄-alkoxy, such as methoxy, halogen and / or trifluoromethyl, benzoyl, naphthoyl or phenyl-C₁-C₄-alkanoyl, unsubstituted pyridylcarbonyl or quinolinylcarbonyl or a group of formula Ia

represents in the R₅ hydrogen, unsubstituted or substituted by hydroxy, mercapto, amino, optionally substituted by hydroxy substituted phenyl, carboxy, carbamoyl or ureido substituted C₁-C₄-alkyl, for example methyl, isopropyl, isobutyl, secondary butyl, hydroxymethyl, mercaptomethyl, 2-methylmercaptoethyl , 3-ureidopropyl, 4-aminobutyl, carboxymethyl, carbamoylmethyl, 2-carboxyethyl, 2-carbamoylethyl, benzyl or 4-hydroxybenzyl, and R₆ C₂-C₇-alkanoyl, such as acetyl, propionyl, butyryl or pivaloyl, means, R₂ 5- bis 7-membered cycloalkyl, in particular cyclohexyl or secondarily cyclopentyl or cycloheptyl, or an unsubstituted or substituted by C₁-C₄-alkyl, such as methyl, C₁-C₄-alkoxy, such as methoxy, halogen and / or trifluoromethyl, phenyl, naphthyl or Represents pyridyl radical, R₃ is hydrogen, C₁-C₇-alkyl, such as methyl, ethyl, propyl, isopropyl or butyl, isobutyl, secondary butyl or tertiary butyl, carbamoyl, C₂-C₇-alkanoyl, such as acetyl, propionyl, butyryl or pivaloyl, carboxy-C₁-C₄-alkanoyl, such as succinoyl, glutaroyl or adipoyl, or carboxy-C₃-C₅-alkenoyl, such as maleyl, fumaroyl , R₄ is phenyl or naphthyl or unsubstituted pyridyl, unsubstituted or substituted by C₁-C₄-alkyl, such as methyl, C₁-C₄-alkoxy, such as methoxy, halogen and / or trifluoromethyl, or unsubstituted pyridyl, benzofuranyl, indolyl, benzimidazolyl or quinolyl, X₁ is methylene, Hydroxymethylene, C₁-C₄-alkoxymethylene, such as methoxymethylene, ethoxymethylene, propyloxymethylene or butyloxymethylene, carbonyl, di-C₁-C₄-alkoxymethylene, such as dimethoxymethylene, diethoxymethylene, dipropyloxymethylene or dibutyloxymethylene, or represents a direct bond, X₂ for C₁-C₇-C₇ such as methylene or secondarily ethylene or 1,3-propylene, carbonyl or a direct bond and X₃ carbonyl, C₁-C₄-alkylene, such as methylene, ethylene or 1,3-propyl n, carboxy-C₁-C₄-alkylene, such as 1,3- (2-carboxy) propylene, 1,4- (2-carboxy) butylene, 1,4- (3-carboxy) butylene, C₁-C₄-alkoxycarbonyl- C₁-C₄-alkylene, such as 1,3- (2-C₁-C₄-alkoxycarbonyl) propylene, 1,4- (2-C₁-C₄-alkoxycarbonyl) butylene, 1,4- (3-C₁-C₄-alkoxycarbonyl) butylene, 1,5- (2-C₁-C₄-alkoxycarbonyl) pentylene, 1,5- (3-C₁-C₄-alkoxycarbonyl) pentylene or 1,5- (4-C₁-C₄-alkoxycarbonyl) pentylene, where C₁- C₄-alkoxycarbonyl in each case, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl, means carbamoyl-C₁-C₄-alkylene, such as 1,3- (2-carbamoyl) propylene, 1,4- (2-carbamoyl) butylene, 1,4- (3-carbamoyl) butylene, 1,5- (2-carbamoyl) pentylene, 1,5- (3-carbamoyl) pentylene or 1,5- (4-carbamoyl) pentylene, or hydroxymethyl-C₁-C₄-alkylene, such as 1,3- (2-hydroxymethyl) propylene, 1,4- (2-hydroxymethyl) butylene, 1,4- (3-hydroxymethyl) butylene, 1,5- (2-hydroxymethyl) pentylene, 1,5- (3rd -Hydroxymethyl) pentylene or 1,5- (4-hydroxymethyl) pentylene, and their salts.

The invention preferably relates to compounds of formula I, wherein R₁ unsubstituted or by C₁-C₄-alkyl, such as methyl, C₁-C₄-alkoxy, such as methoxy, halogen of atomic number up to and including 35, such as chlorine, and / or trifluoromethyl mono- or means disubstituted benzoyl or unsubstituted naphthoyl or phenyl-C₁-C₄-alkanoyl, R₂ is unsubstituted or by C₁-C₄-alkyl, such as methyl, C₁-C₄-alkoxy, such as methoxy, halogen of atomic number up to and including 35, such as chlorine, and / or trifluoromethyl represents mono- or disubstituted phenyl or unsubstituted pyridyl, R₃ represents hydrogen, C₁-C₄-alkyl, such as methyl, ethyl, propyl or isopropyl, carbamoyl or C₂-C₇-alkanoyl, such as acetyl, propionyl, butyryl or pivaloyl, R₄ unsubstituted or by C₁-C₄-alkyl, such as methyl, C₁-C₄-alkoxy, such as methoxy, halogen or Atom number up to and including 35, such as chlorine, and / or triluormethyl means mono- or disubstituted phenyl or unsubstituted naphthyl, pyridyl, benzofuranyl, indolyl, benzimidazolyl or quinolyl, X₁ represents methylene, hydroxymethylene, carbonyl or a direct bond, X₂ for a direct bond is and X₃ is C₁-C₄ alkylene, such as methylene or secondarily ethylene or 1,3-propylene, and their salts.

The invention relates primarily to compounds of formula I, wherein R₁ unsubstituted or by C₁-C₄-alkyl, such as methyl, C₁-C₄-alkoxy, such as methoxy, halogen of atomic number up to and including 35, such as chlorine, and / or trifluoromethyl mono - or disubstituted benzoyl or unsubstituted naphthoyl, R₂ represents unsubstituted or by halogen of atomic number up to and including 35, such as chlorine and / or trifluoromethyl mono- or disubstituted phenyl, R₃ represents hydrogen, R₄ represents unsubstituted quinolyl, X₁ represents methylene, X₂ represents a direct bond and X₃ is C₁-C₄-alkylene, such as methylene or secondarily ethylene or 1,3-propylene, and their salts.

The invention relates in particular to the compounds of the formula I and their salts mentioned in the examples.

• a) in eine Verbindung der Formel II
  
  worin R₂, R₃, R₄, X₁, X₂ und X₃ die angegebenen Bedeutungen haben, den Rest R₁ einführt oder
• b) Verbindungen der Formeln III und IV
  
  worin Y₁ eine Gruppe der Formel -N(R₃)-H und Y₂ Hydroxy, reaktionsfähiges verestertes Hydroxy oder, sofern X₃ für Carbonyl steht, verethertes Hydroxy darstellt oder Y₁ Hydroxy, reaktionsfähig verestertes Hydroxy oder, sofern X₂ Carbonyl bedeutet, verethertes Hydroxy und Y₂ eine Gruppe der Formel -N(R₃)-H darstellt, wobei R₂, R₃, R₄, X₁, X₂ und X₃ die angegebenen Bedeutungen haben, oder deren Salze miteinander kondensiert oder
• c) zur Herstellung von Verbindungen der Formel I, worin einer der Reste X₂ und X₃ Alkylen und der andere Alkylen, Carbonyl oder im Falle von X₂ eine direkte Bindung bzw. im Falle von X₃ einen gegebenenfalls durch Hydroxymethyl oder gegebenenfalls verestertes oder amidiertes Carboxy substituiertes Alkylenrest darstellt, in einer Verbindung der Formel V
  
  worin Z₁ einen in α-Stellung zur Gruppe -N(R₃)- durch Oxo oder Hydroxy substituierten Alkylenrest und Z₂ Alkylen, Carbonyl oder einen gegebenenfalls durch Hydroxymethyl oder gegebenenfalls verestertes oder amidiertes Carboxy substituiertes Alkylenrest bedeutet oder Z₁ Alkylen, Carbonyl oder eine direkte Bindung und Z₂ in α-Stellung zur Gruppe -N(R₃)- durch Oxo oder Hydroxy substituierten Alkylenrest darstellt und R₂, R₃, R₄, X₁, X₂ und X₃ die angegebenen Bedeutungen haben, oder in einem Salz davon die Oxo- bzw. Hydroxygruppe in α-Stellung zur Gruppe -N(R₃)- reduktiv durch Wasserstoff ersetzt bzw. in einer Verbindung der Formel VI
  
  worin Z₃ einen Rest der Formel -C(R_a)=C(R_b)- und Z₄ Alkylen, Carbonyl oder einen gegebenenfalls durch Hydroxymethyl oder gegebenenfalls verestertes oder amidiertes Carboxy substituiertes Alkylenrest bedeutet oder Z₃ Alkylen, Carbonyl oder eine direkte Bindung und Z₄ einen Rest der Formel -C(R_a)=C(R_b)- bedeutet, wobei R_a und R_b jeweils Wasserstoff oder Niederalkyl bedeuten, den Rest der Formel -C(R_a)=C(R_b)- durch Reduktion der Doppelbindung zu dem entsprechenden Rest -CH(R_a)-CH(R_b)- reduziert oder
• d) zur Herstellung von Verbindungen der Formel I, worin X₁ eine Carbonyl- oder Hydroxymethylengruppe bedeutet, Verbindungen der Formeln VII und VIII
  
  worin einer der Reste Y₃ und Y₄ Formyl oder eine gegebenenfalls anhydridisierte oder veresterte Carboxygruppe und der andere einen metallischen Rest darstellt und R₂, R₃, R₄, X₂ und X₃ die angegebenen Bedeutungen haben, miteinander kondensiert oder
• e) zur Herstellung von Verbindungen der Formel I, worin R₃ für Wasserstoff steht, aus einer Verbindung der Formel IX
  
  worin Y₅ eine Aminoschutzgruppe bedeutet und R₂, R₄, X₁, X₂ und X₃ die angegebenen Bedeutungen haben, oder aus einem Salz davon die Gruppe Y₅ abspaltet oder
• f) zur Herstellung von Verbindungen der Formel I, worin X₃ Alkylen bedeutet, Verbindungen der Formeln X und XI
  
  worin Y₆ eine Gruppe der Formel -N(R₃)-H, Y₇ Wasserstoff, Y₈ und Y₉ gemeinsam Oxo und Z₅ einen X₂ entsprechenden Alkanylylidenrest bedeuten oder Y₆ und Y₇ gemeinsam Oxo, Y₈ eine Gruppe der Formel -N(R₃)-H, Y₉ Wasserstoff und Z₅ einen Rest X₃ darstellt, unter reduzierenden Bedingungen miteinander kondensiert und gewünschtenfalls eine erhaltene Verbindung in eine andere Verbindung der Formel I überführt, ein verfahrensgemäss erhältliches Isomerengemisch in die Komponenten auftrennt und das jeweils bevorzugte Isomere abtrennt und/oder eine verfahrensgemäss erhältliche freie Verbindung in ein Salz oder eine verfahrensgemäss erhältliches Salz in die entsprechende freie Verbindung überführt.

The invention further relates to a method based on methods known per se for producing the compounds according to the invention. This is characterized in that one

• a) in a compound of formula II
  
  wherein R₂, R₃, R₄, X₁, X₂ and X₃ have the meanings given, the rest introduces R₁ or
• b) compounds of the formulas III and IV
  
  wherein Y₁ is a group of the formula -N (R₃) -H and Y₂ hydroxy, reactive esterified hydroxy or, if X₃ is carbonyl, etherified hydroxy or Y₁ hydroxy, reactive esterified hydroxy or, if X₂ is carbonyl, etherified hydroxy and Y₂ one Group of the formula -N (R₃) -H represents, where R₂, R₃, R₄, X₁, X₂ and X₃ have the meanings given, or their salts condensed with one another or
• c) for the preparation of compounds of formula I in which one of the radicals X₂ and X₃ alkylene and the other alkylene, carbonyl or in the case of X₂ a direct bond or in the case of X₃ an alkylene radical optionally substituted by hydroxymethyl or optionally esterified or amidated carboxy represents in a compound of formula V
  
  wherein Z₁ is an α-position to the group -N (R₃) - substituted by oxo or hydroxy alkylene radical and Z₂ alkylene, carbonyl or an alkylene radical optionally substituted by hydroxymethyl or optionally esterified or amidated carboxy or Z₁ alkylene, carbonyl or a direct bond and Z₂ in the α-position to the group -N (R₃) - represents alkylene radical substituted by oxo or hydroxyl and R₂, R₃, R₄, X₁, X₂ and X₃ have the meanings given, or in a salt thereof the oxo or hydroxyl group in α -Position to the group -N (R₃) - reductively replaced by hydrogen or in a compound of formula VI
  
  wherein Z₃ is a radical of the formula -C (R _a ) = C (R _b ) - and Z₄ alkylene, carbonyl or an alkylene radical optionally substituted by hydroxymethyl or optionally esterified or amidated carboxy or Z₃ alkylene, carbonyl or a direct bond and Z₄ one Rest of the formula -C (R _a ) = C (R _b ) -, where R _a and R _b each represent hydrogen or lower alkyl, the rest of the formula -C (R _a ) = C (R _b ) - by reducing the Double bond to the corresponding radical -CH (R _a ) -CH (R _b ) - reduced or
• d) for the preparation of compounds of the formula I in which X₁ is a carbonyl or hydroxymethylene group, compounds of the formulas VII and VIII
  
  wherein one of the radicals Y₃ and Y₄ formyl or an optionally anhydridized or esterified carboxy group and the other represents a metallic radical and R₂, R₃, R₄, X₂ and X₃ have the meanings given, condensed with one another or
• e) for the preparation of compounds of formula I, wherein R₃ is hydrogen, from a compound of formula IX
  
  wherein Y₅ is an amino protecting group and R₂, R₄, X₁, X₂ and X₃ have the meanings given, or from a salt thereof the group Y₅ or
• f) for the preparation of compounds of the formula I in which X₃ is alkylene, compounds of the formulas X and XI
  
  wherein Y₆ is a group of the formula -N (R₃) -H, Y₇ hydrogen, Y₈ and Y₉ together oxo and Z₅ is an alkanylylidene radical corresponding to X₂ or Y₆ and Y₇ together are oxo, Y₈ is a group of the formula -N (R₃) -H, Y₉ is hydrogen and Z₅ is a radical X₃, condensed with one another under reducing conditions and, if desired, a compound obtained is converted into another compound of the formula I, separates a mixture of isomers obtainable according to the process into the components and separates the preferred isomer and / or converts a free compound obtainable according to the process into a salt or a salt obtainable according to the process into the corresponding free compound.

The implementation of the process-related reactions and the production of new starting materials or intermediates is carried out in analogy to the reaction and formation method of known starting materials or intermediates. Even if not expressly mentioned below, the customary auxiliaries, such as catalysts, condensation and solvolysis agents and / or solvents or diluents, and reaction, such as temperature and pressure conditions, and, if appropriate, protective gases are used.

The introduction of the radical R₁ according to process variant a) is carried out in a conventional manner, for example by reaction with an agent introducing the radical R₁, such as an N-acylating agent of the formula R₁-Y _a (IIa1), in which R₁ is an optionally substituted aroyl or heteroaroyl -, Cycloalkylcarbonyl-, Aralkanoyl-, Heteroarylalkanoyl- or Arylcarbamoylrest or the acyl residue of an optionally N-alkanoylated α-amino acid and Y _a optionally etherified hydroxy, such as hydroxy, lower alkoxy or optionally substituted phenoxy, or reactive esterified hydroxy, such as halogen, especially chlorine, or a radical of the formula -O-R₁, or with an aralkylating, aryloxyalkylating or heteroarylalkylating agent of the formula R₁-Y _b (IIa2), in which R₁ is an optionally substituted aralkyl, aryloxyalkyl, heteroaralkyl radical and Y _b reactive esterified Hydroxy, such as halogen, for example chlorine, bromine or iodine, or a sulfonyloxy group , such as an alkane or optionally substituted benzenesulfonyloxy group, for example methane, ethane, benzene, p-toluene or p-bromobenzenesulfonyloxy, or by reaction under reducing conditions with a compound of the formula R₁ = O (IIa3), in which R₁ represents an optionally substituted aralkyl, aryloxyalkyl, heteroaralkyl radical.

If necessary, intermediate decomposition is carried out with thermal decomposition Ammonium salts or in the presence of a condensing agent such as a water-binding agent or basic condensing agent and in the presence of a solvent or diluent. Thus, the reaction with acids of the formula IIa1 (Y = COOH) is preferably carried out in the presence of a water-binding agent, such as N, N-dicyclohexylcarbodiimide, or with thermal decomposition of the primary ammonium salt formed, while the reaction with acid anhydrides of the formula IIa1 (Y = Halogen or -O- (C = O) -R₁) and with compounds of the formula IIa2, preferably in the presence of a basic condensing agent, such as an alkali metal hydroxide or carbonate, or a tertiary or sterically hindered secondary organic amine, such as a tri-lower alkylamine, for example of triethylamine or diisopropylamine, or an aromatic nitrogen base, for example pyridine.

The reaction with compounds of the formula IIa3 is carried out, for example, in the presence of hydrogen and a hydrogenation catalyst, such as a platinum or palladium catalyst or Raney nickel, or in the presence of a light metal hydride, such as sodium borohydride or sodium cyanoborohydride, preferably in an inert under the reaction conditions Solvents, such as a lower alkanol, such as methanol or ethanol, or a di-lower alkyl or lower alkylene ether, such as diethyl ether, dioxane or tetrahydrofuran.

miteinander umsetzt, beispielsweise wie nachstehend unter der Verfahrensvariante b) beschrieben.The starting materials of the formula II can be prepared in a customary manner, for example by using compounds of the formulas

implemented with each other, for example as described below under process variant b) .

In starting materials of formula III or IV according to process variant b), reactive esterified hydroxy means, for example, a halogen, such as chlorine, bromine or iodine atom, or, if X₃ is different from carbonyl, a sulfonyloxy group, for example methanesulfonyloxy or p-toluenesulfonyloxy, or if X₃ is carbonyl, a group of the formula -O- (C = O) -R₄. Etherified hydroxy means for example Lower alkoxy, such as methoxy or ethoxy, or optionally substituted phenyloxy.

The reaction of compounds of the formulas III and IV is carried out in a customary manner, for example with thermal decomposition of intermediately formed ammonium salts or in the presence of a condensing agent, such as a water-binding agent or basic condensing agent, and in the presence of a solvent or diluent. Thus, the reaction with acids of the formula IV or III (Y₂ or Y₁ = OH) is preferably carried out in the presence of a water-binding agent, such as N, N-dicyclohexylcarbodiimide, or with thermal decomposition of the primary ammonium salt, while the reaction with reactive Esters of the formula IV or III (Y₂ or Y₁ = reactive esterified hydroxy) or with acid anhydrides of the formula IV or III (Y₂ or Y₁ = anhydridized hydroxy) preferably in the presence of a basic condensing agent, such as an alkali metal hydroxide or carbonate, or a tertiary or sterically hindered secondary organic amine, such as a tri-lower alkylamine, for example of triethylamine or diisopropylamine, or an aromatic nitrogen base, e.g. of pyridine.

den Rest R₁ einführt, beispielsweise wie vorstehend unter der Verfahrensvariante a) beschrieben.The starting materials of the formula III can be prepared in a customary manner, for example by converting them into a compound of the formula IIIa

introduces the rest R₁, for example as described above under process variant a).

The reductive replacement of the oxo or hydroxy group in the α position to the group -N (R₃) - by hydrogen or the reduction of the double bond in the rest of the formula -C (R _a ) = C (R _b ) - according to the process variant c) is carried out, for example, by catalytic hydrogenation, ie treatment with hydrogen in the presence of a hydrogenation catalyst, such as a metal or a metal compound of a metal from Group VIIIb of the Periodic Table, such as platinum, platinum oxide, palladium / carbon or Raney nickel, or by reaction with a light metal hydride, such as an alkali metal borohydride, for example with sodium cyanoborohydride, or by treatment with formic acid.

worin Z₁′ eine direkte Bindung oder einen um ein C-Atom verkürzten Rest X₂ und Y₁′ Wasserstoff, Niederalkyl oder freies, verethertes oder reaktionsfähiges verestertes Hydroxy bedeutet und Z₂ die angegebene Bedeutung hat, oder von Verbindungen der Formel VIa und VIb

worin Z₁ die angegebene Bedeutung hat, Z₂′ eine direkte Bindung oder einen um ein C-Atom verkürzten Rest X₃ und Y₂′ Wasserstoff, Niederalkyl oder freies, verethertes oder reaktionsfähiges verestertes Hydroxy bedeutet, erhalten werden. Ist in Verbindungen der Formel Va Y₁′ bzw. in Verbindungen der Formel VIb Y₂′ Wasserstoff oder Niederalkyl, werden dabei unter milden Reaktionsbedingungen, insbesondere im basischen oder neutralen Milieu, die entsprechenden Verbindungen der Formel V und unter drastischen Reaktionsbedingungen, insbesondere im sauren Milieu, die entsprechenden Verbindungen der Formel VI gebildet. Im letztgenannten Fall werden dabei intermediär die entsprechenden Verbindungen der Formel V gebildet, aus denen dann durch Wasserabspaltung die entsprechenden Verbindungen der Formel VI gebildet werden. Ausgangsstoffe der Formeln V und VI können auch nebeneinander entstehen. In einer bevorzugten Ausführungsform der Erfindung werden die Zwischenprodukte der Formel V bzw. VI in situ gebildet und ohne Isolierung zu den entsprechenden Verbindungen der Formel I reduziert, indem man die Kondensation von Ausgangsstoffen der Formeln Va und Vb bzw. VIa und VIb in Gegenwart eines der genannten Reduktionsmittel vornimmt.Starting materials of the formulas V and VI can be obtained, for example, by condensation of compounds of the formulas Va and Vb

wherein Z₁ 'is a direct bond or a radical shortened by one C atom X₂ and Y₁' is hydrogen, lower alkyl or free, etherified or reactive esterified hydroxy and Z₂ has the meaning given, or of compounds of the formulas VIa and VIb

wherein Z₁ has the meaning given, Z₂ 'is a direct bond or a radical shortened by one carbon atom X₃ and Y₂' is hydrogen, lower alkyl or free, etherified or reactive esterified hydroxy, are obtained. Is hydrogen or lower alkyl in compounds of the formula Va Y₁ ′ or in compounds of the formula VIb Y₂ ′, the corresponding compounds of the formula V and under drastic reaction conditions, in particular in an acidic medium, under mild reaction conditions, in particular in a basic or neutral environment, the corresponding compounds of formula VI are formed. In the latter case, the corresponding compounds of the formula V are formed intermediately, from which the corresponding compounds of the formula VI are then formed by elimination of water. Starting materials of the formulas V and VI can also occur side by side. In a preferred embodiment of the invention, the intermediates of the formulas V and VI are formed in situ and reduced without isolation to the corresponding compounds of the formula I by condensing starting materials of the formulas Va and Vb or VIa and VIb in the presence of one of the mentioned reducing agent.

In starting materials of the formula VII or VIII for process variant d), anhydride or esterified carboxy Y₃ or Y₄ means, for example, halocarbonyl or in the case of Y₄ a group of the formula R₂-C (= O) -O- and a metallic radical Y₃ or Y₄, for example, an alkali metal atom or a group of the formula -M ^II / 2 or M ^II -Hal, where M ^{II is} a metal atom of Group IIb of the periodic system of the elements, such as Mg or Zn.

The compounds of the formulas VII and VIII are reacted in a customary manner, for example in an ether-like solvent, such as an aliphatic or cycloaliphatic ether, e.g. in diethyl ether, methoxybutane, dibutyl ether, tetrahydrofuran or dioxane.

worin Y₁ eine Gruppe der Formel -N(R₃)-H und Y₂ Hydroxy, reaktionsfähiges verestertes Hydroxy oder, sofern X₃ für Carbonyl steht, verethertes oder anhydridisiertes Hydroxy darstellt oder Y₁ Hydroxy, reaktionsfähig verestertes Hydroxy oder, sofern X₂ Carbonyl bedeutet, verethertes oder anhydridisiertes Hydroxy und Y₂ eine Gruppe der Formel -N(R₃)-H darstellt, wobei R₂, R₃, R₄, X₁, X₂ und X₃ die angegebenen Bedeutungen haben, oder deren Salze miteinander kondensiert, beispielsweise wie unter der Verfahrensvariante b) angegeben.Starting materials of the formula VII, in which Y₃ is formyl or optionally anhydridized or esterified carboxy, are prepared, for example, by using compounds of the formulas VIIa and VIIIa

wherein Y₁ is a group of the formula -N (R₃) -H and Y₂ hydroxyl, reactive esterified hydroxy or, if X₃ is carbonyl, etherified or anhydrideized hydroxy or Y₁ hydroxy, reactive esterified hydroxy or, if X₂ is carbonyl, etherified or anhydrideized Hydroxy and Y₂ is a group of the formula -N (R₃) -H, where R₂, R₃, R₄, X₁, X₂ and X₃ have the meanings given, or their salts are condensed with one another, for example as indicated under process variant b).

worin Y′₃ ein Halogenatom, insbesondere Chlor, Brom oder Jod, bedeutet, mit einem Metall der Formel M^II umsetzt bzw. ausgehend von Verbindungen der Formel Y′₄-R₂ (VIIIb), worin Y′₄ Wasserstoff oder ein Halogenatom, insbesondere Chlor, Brom oder Jod, bedeutet, eine Verbindung der Formel VIIIb, worin Y′₄ Wasserstoff ist mit einer metallorganischen Verbindung, beispielsweise einem Metallderivat eines aliphatischen Kohlenwasserstoffes, z.B. mit Butyllithium, bzw. eine Verbindung der Formel VIIIb, worin Y′₄ ein Halogenatom bedeutet, mit einem Metall der Formel M^II umsetzt.Starting materials of the formulas VII or VIII, in which Y₃ or Y₄ is a metallic radical, are preferably prepared in situ by using a compound of the formula VIIb

wherein Y'₃ is a halogen atom, in particular chlorine, bromine or iodine, with a metal of the formula M ^II or starting from compounds of the formula Y'₄-R₂ (VIIIb), in which Y'₄ is hydrogen or a halogen atom, in particular Chlorine, bromine or iodine means a compound of the formula VIIIb, in which Y′₄ is hydrogen with a organometallic compound, for example a metal derivative of an aliphatic hydrocarbon, for example with butyllithium, or a compound of the formula VIIIb, in which Y′₄ is a halogen atom, is reacted with a metal of the formula M ^II .

In starting materials of formula IX according to process variant e), the amino protecting group Y₅ is, for example, an optionally halogenated lower alkanoyl group, such as trifluoroacetyl, or an acyl group derived from a half ester of carbonic acid, such as a lower alkoxycarbonyl or α-phenyl-lower alkoxycarbonyl group, e.g. Tertiary butyloxycarbonyl or benzyloxycarbonyl, or a silyl group such as tri-lower alkylsilyl, e.g. Trimethylsilyl. The amino protective group is cleaved off in a conventional manner, for example by acid treatment, or starting from compounds IX, in which Y₅ is halogenated lower alkanoyl, such as trifluoroacetyl, by reductive cleavage, for example by treatment with a light metal hydride, such as sodium borohydride, preferably in a lower alkanol, such as methanol .

ausgeht.The starting materials of formula IX can be prepared, for example, in analogy to process variant a), with corresponding compounds of formula IXa

going out.

The reaction of compounds of the formulas X and XI according to process variant f) takes place, for example, by elimination of water, for example by azeotropic distillation, in particular with toluene, and subsequent reduction with borane or a light metal hydride, such as an alkali metal borohydride, e.g. with sodium boranate or sodium cyanoborohydride.

Starting materials of the formula X, in which R₁ is one of the acyl radicals mentioned under formula I, X₁ is hydroxymethylene and Y₆ and Y₇ together are oxo, and their pharmaceutically acceptable salts have the same pharmacological properties and comparable potency as the end products of the formula I.

worin R₁ einen gegebenenfalls substituierten Aroyl-, Heteroaroyl-, Cycloakylcarbonyl-, Aralkanoyl-, Heteroarylalkanoyl-, Aralkoxycarbonyl- oder Arylcarbamoylrest oder den Acylrest einer gegebenenfalls durch Niederalkanoyl oder Carbamoylniederalkanoyl N-substituierten α-Aminosäure bedeutet, R₂ Cycloalkyl oder einen gegebenenfalls substituierten Aryl- oder Heteroarylrest darstellt, X₁ Hydroxymethylen darstellt und Y₆ und Y₇ gemeinsam für Oxo stehen, und ihre Salze, Verfahren zur Herstellung der erfindungsgemässen Verbindungen der Formel X, diese enthaltende pharmazeutische Präparate und ihre Verwendung als Arzneimittelwirkstoffe.Accordingly, the invention also relates to 1-acylpiperidones of the formula X.

wherein R₁ represents an optionally substituted aroyl, heteroaroyl, cycloakylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl radical or the acyl radical which is optionally substituted by lower alkanoyl or carbamoyl-lower alkanoyl, an optionally substituted α-aminoyl or R₂ Heteroarylrest represents, X₁ represents hydroxymethylene and Y₆ and Y₇ together represent oxo, and their salts, processes for the preparation of the compounds of formula X according to the invention, pharmaceutical preparations containing them and their use as active pharmaceutical ingredients.

The variable R₂ preferably has the meaning given for the compounds of the formula I, preferably the above for particularly preferred compounds of the formula I.

The invention relates primarily to those compounds of formula X, wherein R₁ is unsubstituted or by C₁-C₄-alkyl, such as methyl, C₁-C₄-alkoxy, such as methoxy, halogen of atomic number up to and including 35, such as chlorine, and / or trifluoromethyl means mono- or disubstituted benzoyl or unsubstituted naphthoyl, R₂ is unsubstituted or by halogen of atomic number up to and including 35, such as chlorine and / or trifluoromethyl mono- or disubstituted phenyl, X₁ represents hydroxymethylene and Y₆ and Y₇ together represent oxo, and their Salts.

The invention relates in particular to the compounds of the formula X and their salts mentioned in the examples.

mit einem den Rest R₁ einführendem Mittel kondensiert und gewünschtenfalls eine erhaltene Verbindung in eine andere Verbindung der Formel I überführt, ein verfahrensgemäss erhältliches Isomerengemisch in die Komponenten auftrennt und das jeweils bevorzugte Isomere abtrennt und/oder eine verfahrensgemäss erhältliche freie Verbindung in ein Salz oder eine verfahrensgemäss erhältliches Salz in die entsprechende freie Verbindung überführt.The inventive compounds of formula X, wherein R₁ and R₂ have the meanings given, X₁ represents hydroxymethylene and Y₆ and Y₇ together represent oxo, and their salts are prepared by methods known per se. The process according to the invention for their production is characterized in that a compound of formula Xa

condensed with an agent introducing the radical R 1 and, if desired, converting a compound obtained into another compound of the formula I, separating a mixture of isomers which is obtainable according to the process into the components and removing the preferred isomer in each case and / or a free compound which is obtainable according to the process into a salt or a process available salt is converted into the corresponding free compound.

As the R₁ introducing agent, for example, compounds of the formula R₁-Y₁₀ (Xb) are suitable, in which Y₁₀ reactive esterified hydroxy, such as halogen or a sulfonyloxy group, such as benzene, p-toluene or methanesulfonyloxy, or if R₁ aroyl, heteroaroyl -, Cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl radical or the acyl radical of an α-amino acid which is optionally substituted by lower alkanoyl or carbamoyl-lower alkanoyl, etherified hydroxy, such as lower alkoxy or optionally, for example by halogenated and / or nitro , represents.

The reaction is carried out in a conventional manner, for example in the presence of a basic condensing agent such as an alkali metal bicarbonate, e.g. sodium bicarbonate, preferably in a water-containing two-phase system, e.g. in methylene chloride / water.

Compounds of the formula Xa can in turn be prepared by reacting an N-protected piperidin-4-onketal, for example 1- (tertiary butyloxycarbonyl) piperindin-4-one-ethylene ketal, with an aldehyde of the formula R₂-CH = O (Xc), for example in the presence of a metal, such as alkali metal hydrocarbon compound, preferably a lower alkyl lithium compound, for example secondary butyllithium, in particular in an ether-like solvent, such as in diethyl ether, at -30 ° to -80 ° C, for example at -60 ° to -75 ° C.

durch Behandlung mit einem Alkalimetallhydroxid, z.B. mit Kaliumhydroxid in wässrigem Methanol, verseift und decarboxyliert, die erhaltene Säure der Formel Xg

z.B. durch Behandeln mit einem Halogenierungsmittel, wie Oxalylchlorid oder Thionylchlorid, und nachfolgende Umsetzung mit Ammoniak amidiert und anschliessend zum entsprechenden Amin der Formel Xh

abbaut, dieses nach Schutz der Aminogruppe, beispielsweise durch Acylierung, mit einem Niederalkoxymethylhalid der Formel RO-CH₂-Hal (Xi; R= Niederalkyl; Hal= Halogen), z.B. mit Chlordimethylether in Gegenwart von Natriumhydroxid in Dichlormethan/Wasser, kondensiert, das Reaktionsprodukt der Formel Xi

durch Säurebehandlung, beispielsweise Behandlung mit einer Lewissäure, wie Zinntetrachlorid, Eisen-III-chlorid, Titantetrachlorid, oder Protonensäure, wie Schwefelsäure, Chlorsulfonsäure, p-Toluolsulfonsäure oder Trifluormethylessigsäure oder -methansulfonsäure, in Acetonitril und erforderlichenfalls Acetanhydrid und einem weiteren Lösungsmittel, wie Dichlormethan, Benzol oder Toluol, zur entsprechenden N-geschützten Verbindung der Formel Xj

cyclokondensiert, die Aminoschutzgruppe abspaltet, gewünschtenfalls ein erhaltenes Racemat in die Enantiomeren auftrennt, in üblicher Weise die Gruppe R₁, beispeilsweise wie vorstehend für die Herstellung von Verbindungen der Formel X, worin X₁ Hydroxymethylen und Y₆ gemeinsam mit Y₇ Oxo darstellt, beschrieben, einführt und die Aminoschutzgruppe durch Säurebehandlung, beispielsweise mit 6N-Salzsäure, abspaltet.Compounds of the formula X, in which Y Gruppe is a group of the formula -N (R₃) -H and Y₇ is hydrogen, are prepared, for example, by using a compound of the formula R₂-X₁-Y (Xd), in which Y is reactive esterified hydroxy, such as halogen Lower alkanesulfonyloxy or optionally substituted benzenesulfonyloxy means, in the presence of an alkali metal lower alkanolate such as sodium methoxide, in a lower alkanol such as methanol, or in the presence of sodium amide in toluene with a but-2-ene-1,1-dicarboxylic acid lower alkyl ester of the formula CH₂ = CH-CH₂ -CH (COOR) ₂ (Xe; R = lower alkyl) condenses, the reaction product of the formula Xf

by treatment with an alkali metal hydroxide, for example with potassium hydroxide in aqueous methanol, saponified and decarboxylated, the acid of formula Xg obtained

for example by treatment with a halogenating agent, such as oxalyl chloride or thionyl chloride, and subsequent reaction with ammonia and then amidated to the corresponding amine of the formula Xh

degrades this after protection of the amino group, for example by acylation, with a lower alkoxymethyl halide of the formula RO-CH₂-Hal (Xi; R = lower alkyl; Hal = halogen), for example with chlorodimethyl ether in the presence of sodium hydroxide in dichloromethane / water, condensed the reaction product of the formula Xi

by acid treatment, for example treatment with a Lewis acid, such as tin tetrachloride, ferric chloride, titanium tetrachloride, or protonic acid, such as sulfuric acid, chlorosulfonic acid, p-toluenesulfonic acid or trifluoromethyl acetic acid or methanesulfonic acid, in acetonitrile and, if necessary, acetic anhydride and a further solvent, such as dichloride Benzene or toluene, to the corresponding N-protected compound of formula Xj

cyclocondensed, splitting off the amino protecting group, if desired separating a racemate obtained into the enantiomers, in a conventional manner the group R₁, for example as described above for the preparation of compounds of the formula X, in which X₁ represents hydroxymethylene and Y₆ together with Y₇ oxo, and which Amino protecting group is split off by acid treatment, for example with 6N hydrochloric acid.

Compounds obtainable according to the process can be converted in a conventional manner into other compounds of the formula I.

For example, compounds of the formula I in which X₁ is carbonyl can be reduced in a conventional manner to the corresponding compounds of the formula I in which X₁ is hydroxymethylene, for example as in process variant c) or for the preparation of intermediates of the formulas V and VI described. In an analogous manner, compounds of the formula I in which X₁ is hydroxymethylene or X₂ and / or X₃ is carbonyl can also be reduced to the corresponding compounds of the formula I in which X₁, X₂ and / or X₃ is methylene.

In compounds of the formula I obtained, in which X 1 is ketalized carbonyl, the carbonyl group can be released in a conventional manner, for example by acid treatment. Conversely, carbonyl X₁ can be ketalized by reaction with an appropriate alcohol, such as a lower alkanol or a lower alkanediol.

Furthermore, in compounds of formula I obtained, in which R₃ is hydrogen, one can introduce a radical R₃ other than hydrogen, alkyl for example by customary alkylation, carbamoyl for example by condensation with isocyanic acid or a carbamoyl halide and optionally substituted alkanoyl or alkenoyl as indicated by customary acylation . Conversely, in compounds of the formula I obtained in which R₃ is alkyl, in particular methyl, the alkyl group can be split off by treatment with a halogen formate, such as methyl ester.

Furthermore, esterified or amidated carboxy as a substituent of alkanoyl or alkenoyl R₃ or of alkylene X₃ can be hydrolyzed into carboxy or, conversely, free carboxy can be esterified or amidated in the compounds of formula I obtained.

Salts obtained can be converted into the free compounds in a manner known per se, e.g. by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or hydrogen carbonate, or ammonia, or another salt-forming base mentioned above or with an acid, such as a mineral acid, e.g. with hydrogen chloride, or another salt-forming acid mentioned at the beginning.

Salts obtained can be converted into other salts in a manner known per se, acid addition salts e.g. by treatment with a suitable metal salt, such as a sodium, barium or silver salt, another acid in a suitable solvent in which an inorganic salt which forms is insoluble and thus leaves the reaction equilibrium, and base salts by releasing the free acid and renewed Salinization.

The compounds of formula I, including their salts, can also be obtained in the form of hydrates or include the solvent used for the crystallization.

As a result of the close relationship between the new compounds in free form and in the form of their salts, above and below, the free compounds and their salts are also to be understood as meaningful and appropriate, if appropriate, the corresponding salts or free compounds.

Diastereomer mixtures and racemate mixtures obtained can be separated in a known manner into the pure diastereomers or racemates, for example by chromatography and / or fractional crystallization, on account of the physico-chemical differences in the constituents.

Racemates obtained can furthermore be broken down into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, with the aid of microorganisms or by reaction of the diastereomer mixture or racemate obtained with an optically active auxiliary compound, for example corresponding to those in compounds of the formula I. contained acidic, basic or functionally changeable groups with an optically active acid, base or an optically active alcohol, in mixtures of diastereomeric salts or functional derivatives, such as esters, separation thereof into the diastereomers, from which the desired enantiomer in each case in the usual manner can be released. Suitable bases, acids or alcohols are, for example, optically active alkaloid bases, such as strychnine, cinchonine or brucine, or D- or L- (1-phenyl) ethylamine, 3-pipecolin, ephedrine, amphetamine and similar synthetically accessible bases, optically active carbon - or sulfonic acids, such as quinic acid or D- or L-tartaric acid, D- or L-di-o-toluyltartaric acid, D- or L-malic acid, D- or L-mandelic acid, or D- or L-camphorsulfonic acid, or optically active alcohols, such as borneol or D- or L- (1-phenyl) ethanol.

The invention also relates to those embodiments of the process according to which one starts from a compound obtainable as an intermediate at any stage of the process and carries out the missing steps or uses a starting material in the form of a salt or in particular forms under the reaction conditions.

The new starting materials which have been specially developed for the preparation of the compounds according to the invention, in particular the starting material selection leading to the compounds of the formula I initially identified as preferred, which form processes for their preparation and their use as intermediates also an object of the invention.

The new compounds of formula I can e.g. in the form of pharmaceutical preparations are used which contain a therapeutically effective amount of the active substance, optionally together with inorganic or organic, solid or liquid, pharmaceutically usable excipients which are suitable for enteral, e.g. oral, or parenteral administration are suitable. Thus, tablets or gelatin capsules are used which contain the active ingredient together with diluents, e.g. Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Tablets can also contain binders, e.g. Magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone, and, if desired, disintegrants, e.g. Starches, aqar, alginic acid or a salt thereof, e.g. Sodium alginate, and / or effervescent mixtures, or absorbents, colors, flavors and sweeteners. Furthermore, the new compounds of formula I can be used in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these being e.g. in lyophilized preparations which contain the active substance alone or together with a carrier material, e.g. Mannitol can be prepared before use. The pharmaceutical preparations can be sterilized and / or adjuvants, e.g. Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, can contain further pharmacologically active substances, are used in a manner known per se, e.g. produced by means of conventional mixing, granulating, coating, solution or lyophilization processes and contain from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilisates to about 100% of the active ingredient.

The invention also relates to the use of the compounds of the formula I, preferably in the form of pharmaceutical preparations. The dosage can depend on various factors, such as the mode of administration, species, age and / or individual condition. The daily doses for oral administration are between about 0.25 and about 10 mg / kg and for warm-blooded animals with a body weight of about 70 kg, preferably between about 20 mg and about 500 mg.

The following examples serve to illustrate the invention; Temperatures are given in degrees Celsius, pressures in mbar.

Example 1 : (2R, 4S) and (2R, 4R) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-phenethyl) -4-piperidine hydrochloride

als gelbes Öl. Dieses wird mit dem Elutionsmittelgemisch Methylenchlorid/Methanol/conc. Ammoniak (97.5:2.25:0.25) zur Trennung der Diastereomeren an Kieselgel chromatographiert, wobei man die Diastereomeren als freie Basen rein erhält.To a mixture of 3.65 g (11.4 mmol) (2R, 4RS) -2-benzyl-1- (3,5-dimethylbenzoyl) -4-piperidinamine in 30 ml methanol, 935 mg (11.4 mmol) sodium acetate, 0.65 ml (11.4 mmol) of acetic acid and 1.44 g (12 mmol) of phenylacetaldehyde are added in portions under nitrogen at 0 ° for 10 minutes in portions of 1.26 g (17.1 mmol) of sodium cyanoborohydride (85%). The reaction mixture is then stirred for 3 hours at room temperature, a further 0.376 g (2.4 mmol) of phenylacetaldehyde are added and the mixture is stirred at 4 ° for 16 hours. The methanol is removed on a rotary evaporator and the reddish reaction mixture is partitioned between ether and 1N sodium bicarbonate solution. The organic phases are washed with brine, dried over magnesium sulfate and evaporated to dryness. A mixture of the hydrochlorides of the title compounds of the formulas is obtained

as a yellow oil. This is mixed with the eluent mixture methylene chloride / methanol / conc. Ammonia (97.5: 2.25: 0.25) for the separation of the diastereomers is chromatographed on silica gel, the diastereomers being obtained as free bases.

TLC: methylene chloride / methanol (98: 2)
Diastereomer A (2R, 4R): R _f = 0.16, mp. 248-249 ° C, [α] _D = -56.9 ° (c = 0.946, methanol),
MS: M⁺ = 426 (free base).
Diastereomer B (2R, 4S): R _f = 0.06, mp. 270 ° C (decomposition), [α] _D = + 30.6 ° (c = 0.759, methanol), MS: M⁺ = 426 (free base).

The starting connections for this are made as follows:

a) (R) -3-Benzylamino-4-phenylbutyric acid ethyl ester

A solution of 42.2 g (0. 203 mol) of (R) -3-amino-4-phenylbutyric acid ethyl ester obtainable by esterification of the known (R) -3-amino-4-phenylbutyric acid with ethanol, 11.6 ml (0.203 mol) of glacial acetic acid, 33.3 g (0.406 mol) sodium acetate and 20.9 ml (0.207 mol) benzaldehyde in 400 ml methanol are added in portions at -5 to 5 ° with a total of 19.1 g sodium cyanoborohydride (0.304 mol). After the addition is complete, the mixture is left to react for 1 hour at room temperature. The yellow suspension is concentrated almost completely on a rotary evaporator and the pulpy residue is distributed between ethyl acetate and water, which is adjusted to a pH of about 8 with ammonia solution. The organic phases are washed neutral with water and brine, dried over magnesium sulfate and evaporated to dryness to give a yellow oil. This is chromatographed on silica gel with methylene chloride / methanol 99: 1, the title compound of the formula being obtained as a pale yellow oil. The oxalate is obtained by adding oxalic acid to an ethereal solution of the title compound.

Mp 142-143 °.
TLC: methylene chloride / methanol (95: 5): R _f = 0.63
MS: M⁺- 91 = 206 (60%)
[α] _D = + 3 ° (c = 1, ethanol) free base
[α] _D = - 0.8 ° (c = 1, CHCl₃) oxalate

b) (R) -N-Benzyl-N - [(1-ethoxycarbonylmethyl-2-phenyl) ethyl] carbamoyl-acetic acid methyl ester

To a solution of 115.8 g (0.389 mol) of (R) -3-benzylamino-4-phenylbutyric acid ethyl ester, 56.8 ml (0.408 mol) of triethylamine and 366 mg of dimethylaminopyridine in 630 ml of toluene, cooled in an ice water bath, is added dropwise over the course of 2 1/2 hours a solution of 43.8 ml (0.408 mol) of methyl malonate in 480 ml of toluene so that the temperature remains within 0-5 °. The suspension is left for 2 hours react completely and then pour it onto 500 ml of ice water. The organic phase is separated off, washed successively with 0.1N hydrochloric acid solution, 1N sodium bicarbonate solution and ice water, then dried over sodium sulfate and concentrated to dryness. The resulting yellow oil is chromatographed on silica gel with ethyl acetate / hexane (1: 2) to give the title compound.

TLC: ethyl acetate / hexane (1: 2), R _f = 0.25
MS: M⁺ = 397 (3%)
[α] _D = + 19.5 ° (c = 1.3, CHCl₃)

c) (6R) -1,6-dibenzyl-2,4-dioxo-3-piperidinecarboxylic acid methyl ester

To a solution of 53.9 g (0.135 mol) of (R) -N-benzyl-N - [(1-ethoxycarbonylmethyl-2-phenyl) ethyl] carbamoyl-acetic acid methyl ester in 520 ml of tert-butanol is added 15.2 g ( 0.135 mol) potassium tert-butanolate and allowed to react for 1 hour. The light yellow suspension is mixed with 1 equivalent (8.1 g) of glacial acetic acid at room temperature and concentrated to a total volume of about 100 ml. The concentrate is diluted with 300 ml of water and extracted 3 times with 300 ml of ethyl acetate. The organic phases are then washed with water and brine, the combined organic phases are dried over sodium sulfate and evaporated to dryness, the title compound being obtained as a clear, yellow oil which is used without further purification; DC. Ethyl acetate / methanol (1: 1); R _f = 0.3.

d) (6R) -1,6-dibenzyl-2,4-piperidinedione

A solution of 106.1g (0.301 mol) of (6R) -1,6-dibenzyl-2,4-dioxo-3-piperidinecarboxylic acid methyl ester in 298 ml of toluene and 445 ml of 10% (vol / vol) acetic acid is added during 2 1 / Heated to 80 ° for 2 hours. The reaction mixture is cooled to room temperature, neutralized by adding 48 g of solid sodium carbonate with ice-water cooling, the phases are separated and the aqueous phase is extracted again with 300 ml of ethyl acetate. The combined organic phases are washed with water and with saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness. The resulting oil is crystallized from ether to give the title compound.

97-97.5 °
TLC: ethyl acetate / hexane (2: 1), R _f = 0.31
[α] _D : + 166.9 ° (c = 1, CHCl₃)
MS: M⁺ = 293 (2.4%)

e) (2R, 4RS) -1,2-dibenzyl-4-piperidinamine ( Variant e1) e1a) 6R) - 1,6-dibenzyl-4- (methoxyimino) -2-piperidone

A solution of 10 g (0.034 mol) of (6R) -1,6-dibenzyl-2,4-piperidinedione in 68 ml of pyridine is mixed with 3.09 g (0.037 mol) of methoxyamine hydrochloride and heated to 85 ° for 1 hour. The clear yellow solution is poured onto ice-cold 1N hydrochloric acid solution (pH approx. 3) and extracted with toluene. The organic extracts are washed with 1N hydrochloric acid solution, then with 1N sodium carbonate solution and with brine. The mixture is then dried over sodium sulfate and concentrated to dryness, the title compound being obtained in the form of waxy crystals.

M.p. 63-77 °
TLC: ethyl acetate / hexane (1: 1), R _f = 0.52
MS: M⁺: 322 (1.4%)

Due to the ¹H-NMR (CDCl₃) is a syn / anti mixture in the ratio of about 7: 3, methoxy signals of the oxime ether at 3.92 or 3.88 ppm.

e1b) (2R, 4RS) -1,2-dibenzyl-4-piperidinamine

A solution of 9.19 g (0.0285 mol) of (6R) -1,6-dibenzyl-4- (methoxyimino) -2-piperidone in 90 ml of tetrahydrofuran under argon is heated in a distillation apparatus with a Vigreux column and a condenser with 40 ° warm water to reflux. 6.1 ml (0.0643 mol) of borane / dimethyl sulfide complex are added dropwise to this solution within 20 minutes, followed by a second addition of 9 ml (0.0949 mol) of borane / dimethyl sulfide complex within 4 hours. During the addition of the borane / dimethyl sulfide complex, the dimethyl sulfide released escapes through the distillation apparatus.

When the addition is complete, the reaction mixture is cooled to 0-4 ° in an ice water bath and excess borane is hydrolyzed by slowly adding a total of 20 ml of methanol.

After the violent, exothermic hydrolysis has subsided, the solvents are removed directly from the apparatus in a water jet vacuum. The residue is then boiled for 2 hours after the addition of 90 ml of 5N hydrochloric acid solution. The solution, cooled to room temperature, is diluted with 200 ml of water, extracted with ether to remove the acid and neutral parts, then the water phase is cooled in an ice water bath, adjusted to pH approx. 9 with 5N sodium hydroxide solution and the base part is extracted with ether / tetrahydrofuran ( 2: 1). The organic extracts are dried over magnesium sulfate and concentrated to dryness, the crude base being obtained in the form of a yellowish oil. This is used directly in the next stage; TLC: methylene chloride / methanol / conc. Ammonia (90: 10: 0.4), R _f = 0.3.

By dissolving in methanolic hydrochloric acid solution and adding ether, amorphous dihydrochloride of the title compound is precipitated; M.p. 150-182 °.

Variant e2) e2a) (6R) -1,6-dibenzyl-2,4-piperidinedione-4-ethylene ketal

A solution of 30 g (0.102 mol) (6R) -1,6-dibenzyl-2,4-piperidinedione, 50 ml of ethylene glycol and 1.8 g of p-toluenesulfonic acid monohydrate in 800 ml of toluene is heated in a water separator for 3 hours. The solution, cooled to room temperature, is washed with 100 ml of 1N sodium bicarbonate solution and brine, the organic phase is dried over magnesium sulfate and concentrated to dryness, the crude ketal being obtained as an oil. This is chromatographed on silica gel with ethyl acetate and the oil obtained from the chromatography is crystallized from ether, the title compound being obtained in the form of white crystals.

Mp 91-93 °
TLC: ethyl acetate / hexane (3: 1), R _f = 0.53
MS: M⁺: 337

e2b) (2R) -1,2-dibenzyl-4-piperidone ethylene ketal

A solution of 10.2 g (0.0302 mol) (6R) -1,6-dibenzyl-2,4-piperidinedione-4-ethylene ketal in 100 ml of tetrahydrofuran is mixed with argon within 10 minutes with 7.6 ml (0.0756 mol) of borane / dimethyl sulfide complex and heated to reflux for 1h. Then you give to the solution cooled to room temperature, 40 ml of 2N sodium hydroxide solution and heated again to reflux for 2 hours, then removes the tetrahydrofuran on a rotary evaporator and extracts the reaction mixture with ether. The organic extracts are washed with sodium bicarbonate, dried over magnesium sulfate and evaporated to dryness to give the title compound; TLC: ethyl acetate / hexane (2: 1), R _f = 0.81; MS: M⁺: 323.

e2c) (2R) -1,2-dibenzyl-4-piperidone

A solution of 85.7 g (0.261 mol) of (2R) -1,2-dibenzyl-4-piperidone ethylene ketal in 170 ml of dioxane and 1000 ml of 2.25 M hydrochloric acid solution are heated to 70 ° for 29 hours. The dioxane is then removed in vacuo, the water phase is adjusted to pH about 8 with 30% sodium hydroxide solution while cooling with ice water and extracted with ether. The ether extracts are washed with 1N sodium bicarbonate solution, dried over sodium sulfate and evaporated to dryness, giving the title compound as a reddish oil which, because of its instability, is further processed without further purification; TLC: ethyl acetate / hexane (1: 1); R _f = 0.71; FD-MS: M⁺: 279

e2d) (2R) -1,2-dibenzyl-4- (methoxyimino) piperidine

3 g (0.01071 mol) (2R) -1,2-dibenzyl-4-piperidone, 4.4 g (0.0537 mol) sodium acetate and 942 mg (0.0113 mol) methoxyamine hydrochloride are dissolved in 30 ml ethanol and heated to 60 for 30 minutes °. The ethanol is then removed in vacuo and the residue is partitioned between water and ethyl acetate, the organic extracts are dried over sodium sulfate and concentrated to dryness, giving the crude product. This is chromatographed on silica gel with ethyl acetate / hexane (3: 1), the title compound being obtained in the form of an oil.

TLC: ethyl acetate / hexane (1: 1), Rf₁ = 0.84, Rf₂ = 0.76 ( syn / anti oximether)
MS: M⁺: 308 (1%), M⁺-91: 217 (90%).
1 H-NMR spectrum (CD₃OD), δ (ppm) = 3.85 (s, = N-OCH₃), 3.825 (s): approx. 1: 1

e2e) (2R, 4RS) -1,2-dibenzyl-4-piperidinamine

In a solution of 5.43 g (17.6 mmol) (2R) -1,2-dibenzyl-4 (methoxyimino) piperidine in 60 ml of tetrahydrofuran, 180 ml is condensed at -78 ° over potassium hydroxide dried ammonia gas. 3.7 g (69 mmol) of ammonium chloride and portions of 1.6 g (70.4 mmol) of sodium metal are added to this solution at -70 °. After one hour, 3.7 g of ammonium chloride and 0.6 g of sodium metal are added to the resulting suspension, and the mixture is stirred at -70 ° for 2 hours. The cooling bath is then removed and the ammonia gas is allowed to evaporate.
The residue is partitioned between 1N sodium hydroxide solution and ether, the organic phase is separated off, the aqueous phase is extracted, the organic phases are washed with brine, the combined organic phases are dried over sodium sulfate and evaporated to dryness, the title compound being in the form of a receives yellow oil; TLC: methylene chloride / methanol / conc. Ammonia (90: 9: 1), R _f = 0.33); MS: M⁺ = 280

f) (2R, 4RS) -N- (1,2-dibenzyl-4-piperidyl) trifluoroacetamide trifluoroacetate

A solution of 6.88 g (24.5 mmol) (2R, 4RS) -1,2-dibenzyl-4-piperidinamine in 20 ml methylene chloride is mixed with 5.1 ml (36.8 mmol) trifluoroacetic anhydride in an ice water bath and then stirred at room temperature for one hour. The reaction mixture is evaporated to dryness, the title compound being obtained as a pale yellow foam; TLC: methylene chloride / methanol / conc. Ammonia (190: 9: 1), R _f = 0.41 (cis) or 0.57 (trans) diastereomer; MS: M⁺-91 (benzyl) = 285 (14%).

g) (2R, 4RS) -N- (2-benzyl-4-piperidyl) trifluoroacetamide trifluoroacetate

To a solution of 19.3 g (39.4 mmol) (2R, 4RS) -N- (1,2-dibenzyl-4piperidyl) -trifluoroacetamide-trifluoroacetate in 160 ml of dioxane is added 3.0 g of 10% palladium catalyst on carbon and hydrogenated at room temperature under nitrogen under normal pressure. The reaction mixture is freed from the catalyst via Celite® and the residue is washed with dioxane. The filtrate is evaporated to dryness and dried under high vacuum, giving the title compound which is used without further purification; TLC: methylene chloride / methanol / conc. Ammonia (90: 9: 1) R _f = 0.24 or 0.3 (two weakly separated diastereomers)

h) (2R, 4RS) -N- [2-benzyl-1- (3,5-dimethylbenzoyl) -4-piperidyl] trifluoroacetamide

To a mixture cooled with ice water of 1.39 g (3.44 mmol) (2R, 4RS) -N- (2-benzyl-4-piperidyl) -trifluoroacetamide trifluoroacetate and 10 ml toluene / water (1: 1) 710 mg of solid sodium bicarbonate and 712 mg of 3,5-dimethylbenzoyl chloride are stirred. The reaction mixture is then allowed to warm to room temperature, stirred for a further 2 hours and partitioned between toluene and 1N sodium bicarbonate solution. The organic phases are washed with water, dried over magnesium sulfate and evaporated to dryness. The colorless oil is chromatographed on silica gel using ethyl acetate / hexane 1: 2 to give the title compound. This is used without further cleaning.

TLC: methylene chloride / methanol / conc. Ammonia (190: 9: 1) R _f = 0.5,
(No separation of the two diastereomers under these conditions
MS: M⁺ = 418 (3%), M⁺-91 (43%)

i) (2R, 4RS) -2-benzyl-1- (3,5-dimethylbenzoyl) -4-piperidinamine

A solution of 4.73 g (10.4 mmol) (2R, 4RS) -N- [2-benzyl-1- (3,5-dimethylbenzoyl) -4-piperidyl] trifluoroacetamide in 50 ml of tetrahydrofuran / methanol 1: 1 is at room temperature 4.1 ml of 5N sodium hydroxide solution are added under nitrogen and the mixture is heated under reflux for 3 hours. When the reaction is complete, the reaction mixture is cooled in ice water, adjusted to pH about 1 with 1N hydrochloric acid solution and the organic solvents are removed on a rotary evaporator. The remaining acidic water phase is first extracted with ether to remove the acid and neutral parts, then it is adjusted to pH approx. 10 with ice water cooling by adding 10N sodium hydroxide solution and extracted with ether. The organic phases are washed with brine, dried over sodium sulfate and evaporated to dryness, the free base being obtained as a brownish oil which can be used without further purification; TLC: methylene chloride / methanol / conc. Ammonia (90: 9: 1) R _f = 0.29; MS: M⁺ = 322 (0.03%), M⁺-91 = 231 (62%).

Analogously, starting from L-phenylalaninol according to the above reaction sequence (2S, 4RS) -2-benzyl-1- (3,5-dimethylbenzoyl) -4-piperidinamine.

Example 2 : (2R *, 4S *) - 2-benzyl-1- (2-naphthoyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weisser Schaum erhalten. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.34, FD-MS: M⁺= 485.The solution of 106 mg (0.182 mmol) (2R *, 4S *) - 2-benzyl-1- (2-naphthoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine in 1.5 ml of methanol are added to 0 mg 28 mg (0.73 mmol) of sodium borohydride in three portions and the mixture was then stirred at 0 ° for 3 hours. The reaction mixture is then mixed with 0.06 ml (0.81 mmol) of acetone and stirred for 10 minutes. The methanol is removed on a rotary evaporator and the solid white residue is partitioned between ethyl acetate and water. The organic phases are washed with brine, dried over magnesium sulfate and evaporated to dryness. The white foam obtained is washed with methylene chloride / methanol / conc. Ammonia (1500: 50: 1) chromatographed on silica gel. It becomes the title compound of the formula

preserved as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.34, FD-MS: M⁺ = 485.

The starting connection for this is established as follows:

a) 2-Benzyl-N-benzyloxycarbonyl-2,3-dihydro-4- (1H) pyridone

165 ml (1.16 mol) of benzyl chloroformate are added dropwise within 20 minutes to the solution of 104 g (0.95 mol) of 4-methoxypyridine in 1 l of anhydrous tetrahydrofuran at -70 ° under argon. The thick beige suspension is then diluted with 200 ml of anhydrous tetrahydrofuran. Now the Grignard reagent, prepared in 160 ml of anhydrous ether from 35.5 g (1.46 mol) of magnesium turnings and 460 ml (1.46 mol) of a 3 molar solution of benzyl chloride in anhydrous ether, is added dropwise to the reaction mixture over 75 minutes and the temperature is kept at -70 °. After a further 10 minutes, the mixture is allowed to warm to room temperature. It is diluted with 500 ml of ether, 900 ml of 4N hydrochloric acid are added dropwise and the phases are separated. The organic phases are washed with water and brine, dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel using hexane / ethyl acetate (3: 1). The title compound is obtained as a colorless viscous oil. TLC: hexane / ethyl acetate (1: 3) R _f = 0.7, IR: 1725, 1665, 1602 cm -1.

b) (2R *, 4R *) - 2-benzyl-4-hydroxy-piperidine

150 g (0.467 mol) of 2-benzyl-N-benzyloxycarbonyl-2,3-dihydro-4- (1H) -pyridone are hydrogenated in 1.51 methanol with 7.5 g Pd / C (10%) as catalyst, then 50 is added g Raney nickel and another 200 ml of methanol and allow to hydrogenate. After filtration, the mixture is concentrated on a rotary evaporator and the brownish oil with methylene chloride / methanol / conc. Ammonia (60: 10: 1) chromatographed on silica gel. The title compound is obtained as a semicrystalline mass which is used without further purification. Crystallization of a sample from ether / hexane gave white crystals of mp 111-112 °. TLC: methylene chloride / methanol / conc. Ammonia (40: 10: 1) R _f = 0.55, FD-MS: M⁺ = 191.

c) (2R *, 4R *) - 2-benzyl-1-t-butyloxycarbonyl-4-hydroxy-piperidine

Allow the solution of 28 g (146 mmol) of (2R *, 4R *) - 2-benzyl-4-hydroxy-piperidine and 35.1 g (161 mmol) of di-t-butyl dicarbonate ert. in 500 ml of chloroform at 50 ° stir for 20 hours. It is then concentrated on a rotary evaporator and the yellow oil on silica gel with methylene chloride / methanol / conc. Ammonia (2000: 50: 1) chromatographed. The title compound is obtained as a yellow oil. TLC: methylene chloride / methanol / conc. Ammonia (2000: 50: 1) R _f = 0.43, FD-MS: M⁺ = 291.

d) (2R *, 4R *) - 2-benzyl-1-t-butyloxycarbonyl-4-methanesulfonyloxypiperidine

To a solution of 62.4 g (214 mmol) of (2R *, 4R *) - 2-benzyl-1-t-butyloxycarbonyl-4-hydroxypiperidine in 75 ml of pyridine is added dropwise under ice cooling 33.3 ml (428 mmol) of methanesulfonyl chloride. After 30 minutes at 0 °, the suspension is allowed to stir for 3 hours at room temperature. After concentration on a rotary evaporator, the reaction mixture is taken up in ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated on a rotary evaporator. The title compound crystallizes from ether in white crystals; Mp 110-115 °; TLC: toluene / ethyl acetate (4: 1) R _f = 0.42, FD-MS: M⁺ = 369.

e) (2R *, 4S *) - 2-benzyl-1-t-butyloxycarbonyl-piperidine-4-azide

The mixture of 98.9 g (267 mmol) (2R *, 4R *) - 2-benzyl-1-t-butyloxycarbonyl-4-methanesulfonyloxypiperidine, 14.4 g (294 mmol) of lithium azide is left and stir 500 ml of N, N-dimethylformamide for 3 hours at 80 ° under argon. The reaction mixture is diluted with ethyl acetate and washed with water and brine, dried over magnesium sulfate and evaporated to dryness. The brownish oil is chromatographed on silica gel using toluene / ethyl acetate (9: 1) as eluent. The title compound is obtained in a mixture with 2-benzyl-N- t- butyloxycarbonyl-1,2,5,6-tetrahydropyridine (weight ratio = 4.2: 1 according to 1 H-NMR), which is not further separated. TLC: toluene / ethyl acetate (9: 1) R _f = 0.59, FD-MS: M⁺ = 316, IR: 2100, 1685 cm⁻¹.

f) (2R *, 4S *) - 2-benzyl-1-t-butyloxycarbonyl-4-piperidinamine

The mixture of 4.16 g (13.1 mmol) (2R *, 4S *) - 2-benzyl-1- t- butyloxycarbonyl-4-piperidinazide and 0.99 g (3.62 mmol) 2-benzyl-N- t- butyloxycarbonyl-1,2 , 5,6-tetrahydropyridine (calculated on the basis of the 1 H-NMR spectrum) is hydrogenated in 100 ml of methanol with hydrogen and 1 g of 10% Pd / C. When the uptake of hydrogen has ended, the mixture is filtered off and concentrated on a rotary evaporator. The brown oil is washed with methylene chloride / methanol / conc. Ammonia (350: 50: 1) chromatographed on silica gel. The title compound is obtained as a yellow oil. TLC: methylene chloride / methanol / conc. Ammonia (350: 50: 1) R _f = 0.4, FD-MS: M⁺ = 290.

g) (2R *, 4S *) - 2-benzyl-1- t -butyloxycarbonyl-N- (4-quinolylmethyl) -4-piperidinamine

The mixture of 5 g (17.2 mmol) of (2R *, 4S *) - 2-benzyl-1-t-butyloxycarbonyl-4-piperidinamine and 2.7 g (17.2 mmol) of quinoline-4-caoxaldehyd is stirred in 50 ml toluene at room temperature and after 2 hours with 2.8 g (23.3 mmol) of anhydrous magnesium sulfate. After a further 16 hours, the mixture is filtered and the filtrate is concentrated. The brown oil is dissolved in 50 ml of methanol and mixed with 0.69 g (18.3 mmol) of sodium borohydride in 4 portions. After 3 hours of stirring at room temperature, the reaction mixture is concentrated, taken up in ethyl acetate and washed with water and brine. The organic phases are dried over magnesium sulfate and evaporated to dryness. The brown oil is washed with methylene chloride / methanol / conc. Ammonia (850: 50: 1) chromatographed on silica gel. The title compound is obtained as a yellow oil. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.38, FD-MS: M⁺ = 431.

h) (2R *, 4S *) - 2-benzyl-1-t-butyloxycarbonyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

The solution of 6.2 g (14.4 mmol) (2R *, 4S *) - 2-benzyl-1- t- butyloxycarbonyl-N- (4-quinolylmethyl) -4-piperidinamine and 2.6 ml (18.7 mmol) triethylamine in 60 ml methylene chloride 2.2 ml (15.8 mmol) of trifluoroacetic anhydride are added at 0 ° under argon and the reaction mixture is stirred at 0 ° for 3 hours. It is diluted with methylene chloride and washed with water. The organic phases are dried over magnesium sulfate and evaporated to dryness. The title compound is obtained as a DC-pure product as a yellow oil. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.62, DCI-MS: (M + H) ⁺ = 528.

i) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Under ice cooling, to 7.73 g (14.7 mmol) of (2R *, 4S *) - 2-benzyl-1-t-butyloxycarbonyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine 250 ml of 6N hydrogen chloride in dioxane added dropwise over 3 minutes and the mixture was then stirred at room temperature for 1 hour. The reaction mixture is concentrated on a rotary evaporator, made basic with 1N sodium hydrogen carbonate solution and extracted with methylene chloride. The organic phases are dried over magnesium sulfate and evaporated to dryness. The brownish oil (7.14 g) is washed with methylene chloride / methanol / conc. Ammonia (700: 50: 1) chromatographed on silica gel. The title compound is obtained as a yellow oil. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.42, DCI-MS: (M + H) ⁺ = 428, IR: 1690 cm⁻¹.

j) (2R *, 4S *) - 2-benzyl-1- (2-naphthoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

To the solution of 97 mg (0.56 mmol) of 2-naphthoic acid in 1 ml of toluene, the solution of 58 μl (0.795 mmol) of thionyl chloride in 0.2 ml of toluene is added dropwise under argon at 50 ° for 10 minutes and the reaction mixture is stirred at 80 ° for 2 hours. It is then concentrated on a rotary evaporator, mixed twice with 1 ml of toluene and concentrated again. The brown oil is dissolved in 1 ml of methylene chloride and is added under argon at 0 ° to a solution of 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl -4-piperidinamine and stirred for 2 hours at 0 °. Then it will Reaction mixture is mixed with water and extracted with methylene chloride. The organic phases are washed with brine, dried over magnesium sulfate and evaporated to dryness. The yellow oil is washed with methylene chloride / methanol / conc. Ammonia (1000: 50: 1) chromatographed on silica gel. The title compound is obtained as a yellow oil. TLC: methylene chloride / methanol / conc. Ammonia (2000: 50: 1) R _f = 0.36, FD-MS: M⁺ = 581.

Example 3: (2R *, 4S *) - 2-benzyl-1- (3-trifluoromethylbenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine

als gelbes Öl. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.28, FD-MS: M⁺= 503.Analogously to Example 2, 0.184 g (0.307 mmol) (2R *, 4S *) - 2-benzyl-1- (3-trifluoromethylbenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 0.046 g (1.23 mmol) implemented sodium borohydride. The title compound of the formula is obtained

as a yellow oil. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.28, FD-MS: M⁺ = 503.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (3-trifluoromethylbenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 2j, 106 mg (0.56 mmol) of 3-trifluoromethylbenzoic acid are first treated with 58 µl (0.795 mmol) of thionyl chloride and then with 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine converted to the product. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.56, FD-MS: M⁺ = 599.

Example 4: (2R *, 4S *) - 2-Benzyl-1- (3,5-bis- (trifluoromethyl) benzoyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.21, FD-MS: M⁺= 571.Analogously to Example 2, 0.271 g (0.406 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-bis- (trifluoromethyl) -benzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl- 4-piperidinamine reacted with 0.061 g (1.23 mmol) sodium borohydride. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.21, FD-MS: M⁺ = 571.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (3,5-bis- (trifluoromethyl) benzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

For the solution of 200 mg (467 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine and 113 mg (561 mmol) 3,5-bis- ( trifluoromethyl) benzoic acid in 3 ml of methylene chloride, 143 mg (561 mmol) of bis- (2-oxo-3-oxazolidinyl) -phosphinic acid chloride and 144 μl (1.03 mmol) of triethylamine are added and the reaction mixture is stirred for 16 hours at room temperature. The mixture is then diluted with methylene chloride and the organic phase is washed once with 10% citric acid, 1N sodium hydrogen carbonate solution and with brine, dried over magnesium sulfate and evaporated to dryness. The yellowish foam is washed with methylene chloride / methanol / conc. Ammonia (1000: 50: 1) chromatographed on silica gel. The title compound is obtained as a yellow oil. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.34, FD-MS: M⁺ = 667.

Example 5: (2R *, 4S *) - 2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.23, DCI-MS: (M+H)⁺ = 496.Analogously to Example 2, 250 mg (0.423 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 64 mg (1.69 mmol) sodium borohydride reacted. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.23, DCI-MS: (M + H) ⁺ = 496.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 4, 200 mg (0.467 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 102 mg (0.561 mmol) 3,5-dimethoxybenzoic acid, 143 mg (0.561 mmol) of bis- (2-oxo-3-oxazolidinyl) -phosphinic acid chloride and 144 μl (1.03 mmol) of triethylamine. The title compound is obtained as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.31, FD-MS: M⁺ = 591.

Example 6: (2R *, 4S *) - 2-benzyl-1- (1-naphthoyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.35, FD-MS: M⁺= 485.Analogously to Example 2, 200 mg (0.344 mmol) (2R *, 4S *) - 2-benzyl-1- (1-naphthoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 52 mg (1.37 mmol) implemented sodium borohydride. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.35, FD-MS: M⁺ = 485.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (1-naphthoyl) -N- (4-quinolylmethyl) -N-trifuoroacetyl-4-piperidinamine

92 µl (0.655 mmol) of 1-chloro-N, N, 2-trimethyl-1-propen-1-amine are added to the solution of 96 mg (0.561 mmol) of 1-naphthoic acid in 2 ml of dry methylene chloride and the mixture is stirred Mixture for 1 hour at 0 ° and one hour at room temperature. The solution of 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine and 130 μl (0.936 mmol) triethylamine is then added to this yellow solution added dropwise in 3 ml of methylene chloride within 10 minutes at room temperature. After 3 hours of stirring at room temperature, water is added, the organic phase is separated off and washed twice with water. The organic phases are dried over magnesium sulfate and evaporated to dryness. The yellow oil is washed with methylene chloride / methanol / conc. Ammonia (800: 50: 1) chromatographed on silica gel. The title compound is obtained as a yellow oil. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.49, FD-MS: M⁺ = 581.

Example 7: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum; DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.37; FD-MS: M⁺=503.Analogously to Example 2, 1.21 g (2.01 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 0.305 mg (8.06 mmol) sodium borohydride reacted. The title compound is obtained

as a white foam; TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.37; FD-MS: M⁺ = 503.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 2j, 1.11 g (5.85 mmol) of 3,5-dichlorobenzoic acid are first mixed with 0.63 ml (8.77 mmol) of thionyl chloride and then with 1 g (2.34 mmol) (2R *, 4S *) - 2-benzyl-N- (4- quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine converted to the product. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.65, FD-MS: M⁺ = 599.

Example 8: (2R *, 4S *) - 2-benzyl-1- (2-quinolinylcarbonyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.42, FD-MS: M⁺= 486.Analogously to Example 2, 155 mg (0.266 mmol) (2R *, 4S *) - 2-benzyl-1- (2-quinolinylcarbonyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 40 mg (1.06 mmol) implemented sodium borohydride. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.42, FD-MS: M⁺ = 486.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (2-quinolylcarbonyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 2j, 97 mg (0.56 mmol) of quinoline-2-carboxylic acid are first treated with 58 µl (0.795 mmol) of thionyl chloride and then with 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4- quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine converted to the product. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.45, FD-MS: M⁺ = 582.

Example 9: (2R *, 4S *) - 2-benzyl-1- (4-chlorophenylacetyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.48, FD-MS: M⁺= 484.Analogously to Example 2, 256 mg (0.441 mmol) (2R *, 4S *) - 2-benzyl-1- (4-chlorophenylacetyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 66 mg (1.76 mmol) sodium borohydride reacted. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.48, FD-MS: M⁺ = 484.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (4-chlorophenylacetyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 2j, 96 mg (0.56 mmol) of 4-chlorophenylacetic acid are first mixed with 58 µl (0.795 mmol) thionyl chloride and then reacted with 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine to the product. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.39, FD-MS: M⁺ = 580.

Example 10: (2R *, 4S *) - 2-benzyl-1- (benzyloxycarbonyl) -N- (4-quinolylmethyl) -4-piperidinamine

als farbloses Öl. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.43, FD-MS: M⁺= 465.Analogously to Example 2, 80 mg (0.142 mmol) (2R *, 4S *) - 2-benzyl-1- (benzyloxycarbonyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 22 mg (0.57 mmol) Sodium borohydride implemented. The title compound is obtained

as a colorless oil. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.43, FD-MS: M⁺ = 465.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (benzyloxycarbonyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

To dissolve 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine in 4 ml methylene chloride, add 67 µl (0.468 mmol ) Benzyl chloroformate and 72 µl (0.515 mmol) triethylamine and the mixture is stirred at this temperature for 16 hours. Then another 34 µl (0.234 mmol) benzyl chloroformate and 36 µl (0.257 mmol) triethylamine are added and the mixture is stirred for 3 hours at room temperature. The mixture is then diluted with methylene chloride and the organic phase is washed with brine, dried over magnesium sulfate and evaporated to dryness. The oil is washed with methylene chloride / methanol / conc. Ammonia (1000: 50: 1) chromatographed on silica gel. The title compound is obtained as an oil. DC: Methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.61, FD-MS: M⁺ = 561.

Example 11: (2R *, 4S *) - 2-benzyl-1- (2-phenylethyl) -N- (4-quinolylmethyl) -4-piperidinamine

als Öl. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.34, FD-MS: M⁺= 435.Analogously to Example 2, 215 mg (0.494 mmol) (2R *, 4S *) - 2-benzyl-1- (2-phenylethyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 77 mg (1.97 mmol) implemented sodium borohydride. The title compound is obtained

as an oil. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.34, FD-MS: M⁺ = 435.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (2-phenylethyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

209 µl (0.936 mmol) of phenylacetaldehyde are added dropwise within 10 minutes at room temperature to a solution of 100 mg (0.233 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4- piperidinamine, 58 mg (0.702 mmol) sodium acetate, 44 mg (0.702 mmol) sodium cyanoborohydride and 67 µl (1.17 mmol) acetic acid in 2 ml ethanol. The reaction mixture is allowed to stir at room temperature for 16 hours. After evaporation on a rotary evaporator, the residue is taken up in ethyl acetate, the organic phase is washed with water and with brine, dried over magnesium sulfate and evaporated to dryness. The yellow oil is washed with methylene chloride / methanol / conc. Ammonia (2000: 50: 1) chromatographed on silica gel. The title compound is obtained as an oil. TLC: methylene chloride / methanol / conc. Ammonia (2000: 50: 1) R _f = 0.33, FD-MS: M⁺ = 531.

Example 12: (2R *, 4S *) - 2-benzyl-1- (2-naphthylacetyl) -N- (4-quinolylmethyl) -4-piperidinamine

als farbloses Öl. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.27, FD-MS: M⁺= 499.Analogously to Example 2, 160 mg (0.269 mmol) (2R *, 4S *) - 2-benzyl-1- (2-naphthylacetyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 42 mg (1.13 mmol) implemented sodium borohydride. The title compound is obtained

as a colorless oil. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.27, FD-MS: M⁺ = 499.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (2-naphthylacetyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 6, 105 mg (0.561 mmol) of 2-naphthylacetic acid are first mixed with 92 µl (0.655 mmol) of 1-chloro-N, N, 2-trimethyl-1-propen-1-amine and then with 200 mg (0.468 mmol) ( 2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine and 130 µl (0.936 mmol) triethylamine converted to the product. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.56, FD-MS: M⁺ = 595.

Example 13: (2R *, 4S *) - 2-benzyl-1- (4-quinolylmethyl) -N- (4-quinolylmethyl) -4-piperidinamine

als gelbes Öl. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.45, FD-MS: M⁺= 490.Analogously to Example 2, 128 mg (0.225 mmol) (2R *, 4S *) - 2-benzyl-1- (4-quinolylmethyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 34 mg (0.872 mmol) implemented sodium borohydride. The title compound is obtained

as a yellow oil. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.45, FD-MS: M⁺ = 490.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (4-quinolylmethyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 11, 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 88 mg (1.4 mmol) sodium cyanoborohydride, 115 mg (1.4 mmol) sodium acetate, 134 μl (2.34 mmol) acetic acid and 294 mg (1.87 mmol) quinoline-4-carboxaldehyde converted to the product. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.33, FD-MS: M⁺ = 568.

Example 14: (2R *, 4S *) - 2-benzyl-1- (2,4-dichlorobenzyl) -N- (4-quinolylmethyl) -4-piperidinamine

als gelbes Öl. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.25, FD-MS: M⁺= 472.Analogously to Example 2, 128 mg (0.218 mmol) (2R *, 4S *) - 2-benzyl-1- (2,4-dichlorobenzyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 34 mg (0.920 mmol) sodium borohydride reacted. The title compound is obtained

as a yellow oil. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.25, FD-MS: M⁺ = 472.

The starting connection for this is established as follows:

a) (2R *, 4S *) - 2-benzyl-1- (4-quinolylmethyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 11, 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 88 mg (1.4 mmol) sodium cyanoborohydride, 115 mg (1.4 mmol) sodium acetate, 134 μl (2.34 mmol) acetic acid and 294 mg (1.87 mmol) quinoline-4-carboxaldehyde converted to the product. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.33, FD-MS: M⁺ = 568.

Example 15: (2R *, 4S *) - 2-benzyl-1- (2,2-diphenylethyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.28, FD-MS: M⁺= 511.Analogously to Example 2, 170 mg (0.280 mmol) (2R *, 4S *) - 2-benzyl-1- (2,2-diphenylethyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 42 mg (1.12 mmol) sodium borohydride reacted. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.28, FD-MS: M⁺ = 511.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (2,2-diphenylethyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 11, 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 88 mg (1.4 mmol) sodium cyanoborohydride, 115 mg (1.4 mmol) sodium acetate, 134 μl (2.34 mmol) acetic acid and 335 μl (1.87 mmol) diphenylacetaldehyde to the product. TLC: methylene chloride / methanol / conc. Ammonia (2000: 50: 1) R _f = 0.50, FD-MS: M⁺ = 607.

Example 16: (2R *, 4S *) - 2-benzyl-1- (phenylcarbamoyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.33, FD-MS: M⁺= 450.Analogously to Example 2, 210 mg (0.384 mmol) (2R *, 4S *) - 2-benzyl-1- (phenylcarbamoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 58 mg (1.54 mmol) Sodium borohydride implemented. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.33, FD-MS: M⁺ = 450.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (phenylcarbamoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

To the solution of 72 mg (0.608 mmol) of phenyl isocyanate in 5 ml of toluene is added the solution of 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4 -piperidinamine and the reaction mixture is stirred for 2 hours at 100 °. The white suspension is cooled and filtered. The title compound is obtained as white crystals with a melting point of 245 ° (decomposition). TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.76, FD-MS: M⁺ = 546.

Example 17: (2R *, 4S *) - 2-benzyl-1- (diphenylacetyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.49, FD-MS: M⁺= 525.Analogously to Example 2, 235 mg (0.378 mmol) (2R *, 4S *) - 2-benzyl-1- (diphenylacetyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 58 mg (1.51 mmol) Sodium borohydride implemented. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.49, FD-MS: M⁺ = 525.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (diphenylacetyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 2j, 248 mg (1.17 mmol) of diphenylacetic acid are first with 128 μl (1.76 mmol) of thionyl chloride and then with 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N -trifluoroacetyl-4-piperidinamine converted to the product. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.45, FD-MS: M⁺ = 621.

Example 18: (2R *, 4S *) - 2-benzyl-1- (2-pyridylacetyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.28, FD-MS: M⁺= 450.Analogously to Example 2, 180 mg (0.329 mmol) (2R *, 4S *) - 2-benzyl-1- (2-pyridylacetyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 50 mg (1.32 mmol) implemented sodium borohydride. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.28, FD-MS: M⁺ = 450.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (2-pyridylacetyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 4, 200 mg (0.467 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 98 mg (0.561 mmol) 2-pyridylacetic acid hydrochloride, 143 mg (0.562 mmol) of bis- (2-oxo-3-oxazolidinyl) -phosphinic acid chloride and 209 μl (1.50 mmol) of triethylamine were reacted. The title compound is obtained as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.60, FD-MS: M⁺ = 546.

Example 19: (2R *, 4S *) - 2-benzyl-1- (4-pyridylacetyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.31, FD-MS: M⁺= 450.Analogously to Example 2, 200 mg (0.366 mmol) (2R *, 4S *) - 2-benzyl-1- (4-pyridylacetyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 55 mg (1.46 mmol) implemented sodium borohydride. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.31, FD-MS: M⁺ = 450.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (4-pyridylacetyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 4, 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 98 mg (0.561 mmol) 4-pyridylacetic acid hydrochloride, 143 mg (0.562 mmol) of bis- (2-oxo-3-oxazolidinyl) -phosphinic acid chloride and 209 μl (1.50 mmol) of triethylamine were reacted. The title compound is obtained as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.56, FD-MS: M⁺ = 546.

Example 20: (2R *, 4S *) - 2-benzyl-1- (2,3-diphenylpropionyl) -N- (4-quinolylmethyl) -4-piperidinamine

als
Diastereomerengemisch in Form von weissem Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.37, FD-MS: M⁺= 539.Analogously to Example 2, 340 mg (0.535 mmol) (2R *, 4S *) - 2-benzyl-1- (2,3-diphenylpropionyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 81 mg (2.14 mmol) sodium borohydride reacted. The title compound is obtained

as
Diastereomer mixture in the form of white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.37, FD-MS: M⁺ = 539.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (2,3-diphenylpropionyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 4, 300 mg (0.702 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 190 mg (0.842 mmol) (R, S) - 2,3-Diphenylpropionic acid, 214 mg (0.842 mmol) of bis- (2-oxo-3-oxazolidinyl) -phosphinic acid chloride and 216 μl (1.54 mmol) of triethylamine. The title compound is obtained as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.74, FD-MS: M⁺ = 635.

Example 21: (2R *, 4S *) - 2-benzyl-1 - ((3S) - (2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-3-yl) carbonyl) - N- (4-quinolylmethyl) -4-piperidinamine

als Diastereomerengemisch in Form von weissem Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (350:50:1) R_f=0.50, FD-MS: M⁺= 529.Analogously to Example 2, 197 mg (0.315 mmol) of the mixture of diastereomers (2R *, 4S *) - 2-benzyl-1 - ((3S) - (2,3,4,9-tetrahydro-1H-pyrido [3,4- b] indol-3-yl) -carbonyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine reacted with 48 mg (1.26 mmol) of sodium borohydride. The title compound is obtained

as a mixture of diastereomers in the form of white foam. TLC: methylene chloride / methanol / conc. Ammonia (350: 50: 1) R _f = 0.50, FD-MS: M⁺ = 529.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1 - ((3S) - (2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-3-yl) carbonyl) - N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

To the solution of 338 mg (0.399 mmol) (2R *, 4S *) - 2-benzyl-1 - ((3S) - (2- (9-fluorenylmethyloxycarbonyl) -2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-3-yl) -carbonyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine in 3 ml of N, N-dimethylformamide, 1.97 ml (19.9 mmol) of piperidine and the mixture is stirred for 2 hours at room temperature. The mixture is then concentrated on a rotary evaporator and the residue is separated with methylene chloride / methanol / conc to separate the diastereomers. Ammonia (2000: 50: 1) chromatographed on silica gel.
TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1)
Diastereomer A: R _f = 0.21, FD-MS: M⁺ = 625,
Diastereomer B: R _f = 0.13, FD-MS: M⁺ = 625.

Example 22: (2R *, 4S *) - 2-benzyl-1- (3-methoxybenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.26, FD-MS: M⁺= 465.Analogously to Example 2 , 230 mg (0.409 mmol) (2R *, 4S *) - 2-benzyl-1- (3-methoxybenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 81 mg (2.14 mmol) implemented sodium borohydride. The title compound of the formula is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.26, FD-MS: M⁺ = 465.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (3-methoxybenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 4, 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 85 mg (0.561 mmol) 3-methoxybenzoic acid, 143 mg (0.561 mmol) of bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride and 144 μl (1.03 mmol) of triethylamine. The title compound is obtained as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.45, FD-MS: M⁺ = 561.

Example 23: (2R *, 4S *) - 2-benzyl-1- (3-N, N-dimethylaminobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.36, FD-MS: M⁺= 478.Analogously to Example 2, 225 mg (0.391 mmol) (2R *, 4S *) - 2-benzyl-1- (3-N, N-dimethylaminobenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine are also used 59 mg (1.56 mmol) of sodium borohydride reacted. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.36, FD-MS: M⁺ = 478.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (3-N, N-dimethylaminobenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 4, 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 93 mg (0.561 mmol) 3-N, N- Dimethylaminobenzoic acid, 143 mg (0.561 mmol) of bis (2-oxo-3-oxazolidinyl) phosphinoyl chloride and 144 μl (1.03 mmol) of triethylamine. The title compound is obtained as a yellow oil. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.65, FD-MS: M⁺ = 574.

Example 24: (2R *, 4S *) - 2-benzyl-1- (cis, cis-3,5-dimethylcyclohexylcarbonyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.24, FD-MS: M⁺= 469.Analogously to Example 2, 195 mg (0.345 mmol) (2R *, 4S *) - 2-benzyl-1- (cis, cis-3,5-dimethylcyclohexylcarbonyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4- piperidinamine reacted with 52 mg (1.38 mmol) of sodium borohydride. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.24, FD-MS: M⁺ = 469.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (cis, cis-3,5-dimethylcyclohexylcarbonyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 4, 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 87 mg (0.561 mmol) cis, cis-3, 5-Dimethylcyclohexylcarboxylic acid (prepared by the method of H. van Bekkum et. Al., Koninkl. Ned. Akad. Wetenschap, Proc. Ser. B. 64 , 161 (1961), 143 mg (0.561 mmol) bis- (2- oxo-3-oxazolidinyl) -phosphinic acid chloride and 144 µl (1.03 mmol) of triethylamine are reacted to give the title compound as a yellow oil TLC: methylene chloride / methanol / concentrated ammonia (1000: 50: 1) R _f = 0.32, FD-MS : M⁺ = 565.

Example 25: (2R *, 4S *) - 2-benzyl-1- (3,5-bis (trifluoromethyl) benzyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.35, FD-MS: M⁺= 557.Analogously to Example 2, 280 mg (28 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-bis- (trifluoromethyl) -benzyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl- 4-piperidinamine reacted with 65 mg (1.71 mmol) of sodium borohydride. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.35, FD-MS: M⁺ = 557.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (3,5-bis- (trifluoromethyl) benzyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl4-piperidinamine

The mixture of 129 ul (0.702 mmol) of 3,5-bis (trifluoromethyl) benzyl bromide, 194 mg (1.40 mmol) of potassium carbonate and 300 mg (0.702 mmol) (2R *, 4S *) - 2-benzyl-N is stirred - (4-Quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine in 3 ml of N, N-dimethylformamide for 17 hours at 60 °. The suspension is then filtered off, well with acetone washed and the filtrate concentrated on a rotary evaporator. The residue is taken up in methylene chloride and washed successively with 10% aqueous citric acid, 1N sodium hydrogen carbonate solution, water and brine and dried over magnesium sulfate. The yellow oil is washed with methylene chloride / methanol / conc. Ammonia (3000: 50: 1) chromatographed on silica gel. The title compound is obtained as a yellow oil. TLC: methylene chloride / methanol / conc. Ammonia (3000: 50: 1) R _f = 0.36, FD-MS: M⁺ = 653.

Example 26: (2S *, 4R *) - 2-benzyl-1- [2- (5-chloro-1H-1,2,4-triazol-1-yl) phenoxyethyl] -N- (4-quinolylmethyl) - 4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.23, FD-MS: M⁺= 553.Analogously to Example 2, 100 mg (0.54 mmol) (2R *, 4S *) - 2-benzyl- [2- (5-chloro-1H-1,2,4-triazol-1-yl) phenoxyethyl] -N- ( 4-Quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine reacted with 23 mg (0.62 mmol) of sodium borohydride. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.23, FD-MS: M⁺ = 553.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- [2- (5-chloro-1H-1,2,4-triazol-1-yl) phenoxyethyl] -N- (4-quinolylmethyl) -N-trifluoroacetyl -4-piperidinamine

Analogously to Example 24, 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 141 mg (0.468 mmol) 2- (5-chloro - (1H-1,2,4-triazol-1-yl) phenoxy) ethyl bromide and 129 mg (0.936 mmol) of potassium carbonate. The title compound is obtained as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.23, FD-MS: M⁺ = 649.

Example 27: Diastereomer A of (2R *, 4S *) - 2-benzyl-1 - ((S) -phenylalanyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.21, FD-MS: M⁺= 478.Analogously to Example 2, 112 mg (0.195 mmol) of the diastereomer A of (2R *, 4S *) - 2-benzyl-1 - ((S) -phenylalanyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4- piperidinamine reacted with 30 mg (0.801 mmol) of sodium borohydride. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.21, FD-MS: M⁺ = 478.

The starting connections for this are made as follows:

a) (2R *, 4S *) - 2-benzyl-1 - ((S) -N-tert-butyloxycarbonyl-phenylalanyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 4, 300 mg (0.702 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 223 mg (0.842 mmol) (S) -N- tert-Butyloxycarbonyl-phenylalanine, 214 mg (0.842 mmol) of bis- (2-oxo-3-oxazolidinyl) -phosphinic acid chloride and 215 μl (1.54 mmol) of triethylamine. The title compound is obtained as a mixture of diastereomers in the form of a yellow oil. TLC: methylene chloride / methanol / conc. Ammonia (2000: 50: 1) R _f = 0.37, FD-MS: M + = 674.

b) Diastereomers of (2R *, 4S *) - 2-benzyl-1 - ((S) -phenylalanyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

To 920 mg (1.36 mmol) (2R *, 4S *) - 2-benzyl-1 - ((S) -N-tert-butyloxycarbonyl-phenylalanyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4- piperidinamine 3.1 ml (4.09 mmol) of trifluoroacetic acid are added and the reaction mixture is stirred for 2 hours at room temperature. The mixture is then concentrated on a rotary evaporator, the residue is taken up in water, made basic at 0 ° C. with 1 N sodium hydrogen carbonate solution and extracted with methylene chloride. The organic phases are washed with brine, dried over magnesium sulfate and evaporated to dryness. The residue is separated with methylene chloride / methanol / conc to separate the diastereomers. Ammonia (2500: 50: 1) chromatographed on silica gel.
TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1)
Diastereomer A: R _f = 0.24, FD-MS: M⁺ = 574,
Diastereomer B: R _f = 0.22, FD-MS: M⁺ = 574.
The mixed fractions of diastereomers A and B were not further separated.

Example 28: Diastereomer B of (2R *, 4S *) - 2-benzyl-1 - ((S) -phenylalanyl) -N- (4-quinolymethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.20, FD-MS: M⁺= 478.Analogously to Example 2, 115 mg (0.200 mmol) of the diastereomer B of (2R *, 4S *) - 2-benzyl-1 - ((S) -phenylalanyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4- piperidinamine reacted with 30 mg (0.801 mmol) of sodium borohydride. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.20, FD-MS: M⁺ = 478.

For the starting compound, see Example 27a.

Example 29: Diastereomer A of (2R *, 4S *) - 2-benzyl-1 - ((R) -phenylalanyl-N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.28, FD-MS: M⁺= 478.Analogously to Example 2, 174 mg (0.303 mmol) of diastereomer A from (2R *, 4S *) - 2-benzyl-1 - ((R) -phenylalanyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine reacted with 46 mg (1,211 mmol) sodium borohydride. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.28, FD-MS: M⁺ = 478.

The starting connections for this are made as follows:

Diastereomers of (2R *, 4S *) - 2-benzyl-1 - ((R) -phenylalanyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 27b, 1.10 g (1.63 mmol) of (2R *, 4S *) - 2-benzyl-1 - ((R) -N-tert-butyloxycarbonyl-phenylalanyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl -4-piperidinamine treated with 3.8 ml (48.8 mmol) of trifluoroacetic acid. The diastereomers of the title compound are obtained. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1)
Diastereomer A: R _f = 0.52, FD-MS: M⁺ = 574,
Diastereomer B: R _f = 0.50, FD-MS: M⁺ = 574.
The mixed fractions of diastereomers A and B were not further separated.

Example 30: Diastereomer B of (2R *, 4S *) - 2-benzyl-1 - ((R) -phenylalanyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (350:50:1) R_f=0.49, FD-MS: M⁺= 478.Analogously to Example 2, 92 mg (0.160 mmol) of the diastereomer B of (2R *, 4S *) - 2-benzyl-1 - ((R) -phenylalanyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4- piperidinamine reacted with 25 mg (0.640 mmol) sodium borohydride. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (350: 50: 1) R _f = 0.49, FD-MS: M⁺ = 478.

For the starting compound, see Example 27a.

Example 31: (2R *, 4S *) - 2-benzyl-1 - ((S) -N-acetyl-phenylalanyl) -N- (4-quinolylmethyl) -4-piperidinamine

als Diastereomerengemisch als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.22, FD-MS: M⁺= 520.Analogously to Example 2, 160 mg (0.259 mmol) of the diastereomer mixture of (2R *, 4S *) - 2-benzyl-1 - ((S) -N-acetyl-phenylalanyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl -4-piperidinamine reacted with 39 mg (1.04 mmol) sodium borohydride. The title compound is obtained

as a mixture of diastereomers as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.22, FD-MS: M⁺ = 520.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1 - ((S) -N-acetyl-phenylalanyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

For the solution of 180 mg (0.313 mmol) of the diastereomer mixture of (2R *, 4S *) - 2-benzyl-1 - ((S) -phenylalanyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine in 2 ml pyridine are 35 µl (0.376 mmol ) Acetic anhydride was added and the mixture was stirred at 0 ° for 2.5 hours. After concentration on a rotary evaporator, the oily residue is taken up in methylene chloride, washed with 5% aqueous citric acid and with 1 N sodium hydrogen carbonate solution. The organic phases are dried over magnesium sulfate and evaporated to dryness. The title compound is obtained as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.39, FD-MS: M⁺ = 616.

Example 32: (2R *, 4S *) - 2-benzyl-1 - ((R) -N-acetyl-phenylalanyl) -N- (4-quinolylmethyl) -4-piperidinamine

als Diastereomerengemisch (weisser Schaum). DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.42, FD-MS: M⁺= 520.Analogously to Example 2, 185 mg (0.411 mmol) of the diastereomer mixture of (2R *, 4S *) - 2-benzyl-1 - ((R) -N-acetyl-phenylalanyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl -4-piperidinamine reacted with 62 mg (1.64 mmol) of sodium borohydride. The title compound is obtained

as a mixture of diastereomers (white foam). TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.42, FD-MS: M⁺ = 520.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1 - ((R) -N-acetyl-phenylalanyl) N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 31, 200 mg (0.348 mmol) of the diastereomer mixture of (2R *, 4S *) - 2-benzyl-1 - ((R) -phenylalanyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine reacted with 39 ul (0.417 mmol) of acetic anhydride. The title compound is obtained as a mixture of diastereomers (white foam). DC: Methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.28, FD-MS: M⁺ = 616.

Example 33: (2R *, 4S *) - 2-benzyl-1 - ((S) -N- (4-carboxamido-butyroyl) phenylalanyl) -N- (4-quinolylmethyl) -4-piperidinamine

als Diastereomerengemisch als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (350:50:1) R_f=0.50, FD-MS: M⁺= 591.Analogously to Example 2, 152 mg (0.221 mmol) of the diastereomer mixture of (2R *, 4S *) - 2-benzyl-1 - ((S) -N- (4-carboxamido-butyroyl) -phenylalanyl) -N- (4- quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine reacted with 34 mg (0.88 mmol) of sodium borohydride. The title compound is obtained

as a mixture of diastereomers as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (350: 50: 1) R _f = 0.50, FD-MS: M⁺ = 591.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1 - ((S) -N- (4-carboxamido-butyroyl) phenylalanyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

For the solution of 200 mg (0.348 mmol) of the mixture of diastereomers of (2R *, 4S *) - 2-benzyl-1 - ((S) -phenylalanyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine in 2 ml of methylene chloride are added at 0 ° 179 μl (1.04 mmol) diisopropylethylamine and 108 mg (0.348 mmol) glutaric acid mono-2,4,5-trichlorophenyl ester amide and the white suspension is stirred for 2 hours at 0 ° and 16 hours at room temperature . After concentrating the now colorless solution on a rotary evaporator, the oily residue is taken up in methylene chloride, washed with 5% aqueous citric acid and with 1 N sodium hydrogen carbonate solution. The organic phases are dried over magnesium sulfate and evaporated to dryness. The title compound is obtained as a white foam. TLC: methylene chloride / methanol / conc. ammonia (1000: 50: 1) R _f = 0.13, FD-MS: M⁺ = 687.

Example 34: (2R *, 4S *) - 2-benzyl-1 - ((R) -N- (4-carboxamido-butyroyl) phenylalanyl) -N- (4-quinolylmethyl) -4-piperidinamine

als Diastereomerengemisch als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (350:50:1) R_f=0.56, FD-MS: M⁺= 591.Analogously to Example 2, 210 mg (0.305 mmol) of the diastereomer mixture of (2R *, 4S *) - 2-benzyl-1 - ((R) -N- (4-carboxamido-butyroyl) -phenylalanyl) -N- (4- quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine reacted with 46 mg (1.22 mmol) of sodium borohydride. The title compound is obtained

as a mixture of diastereomers as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (350: 50: 1) R _f = 0.56, FD-MS: M⁺ = 591.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1 - [(R) -N- (4-carboxamido-butyroyl) phenylalanyl] -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 33, 222 mg (0.386 mmol) of the diastereomer mixture of (2R *, 4S *) - 2-benzyl-1 - [(R) -phenylalanyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 198 ul (1.16 mmol) of diisopropylethylamine and 120 mg (0.386 mmol) of glutaric acid mono-2,4,5-trichlorophenyl ester amide. The title compound is obtained as a mixture of diastereomers as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.38, FD-MS: M⁺ = 687.

Example 35: (2R *, 4S *) - 2-benzyl-1-benzoyl-N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.33, FD-MS: M⁺= 435.Analogously to Example 2, 234 mg (0.440 mmol) (2R *, 4S *) - 2-benzyl-1-benzoyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 67 mg (1.76 mmol) Sodium borohydride implemented. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.33, FD-MS: M⁺ = 435.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1-benzoyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

To dissolve 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine in 4 ml methylene chloride, add 72 µl (0.515 mmol ) Triethylamine and 54 µl (0.468 mmol) benzoyl chloride. The reaction mixture is stirred for 3 hours at 0 °, water is added and the mixture is extracted with methylene chloride. The organic phases are dried over magnesium sulfate and evaporated to dryness. The yellow oil is washed with methylene chloride / methanol / conc. Ammonia (1000: 50: 1) chromatographed on silica gel. The title compound is obtained as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.72, FD-MS: M⁺ = 531.

Example 36: (2R *, 4S *) - 2-benzyl-1- (3-chlorobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine

als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.29, FD-MS: M⁺= 470.Analogously to Example 2, 254 mg (0.449 mmol) (2R *, 4S *) - 2-benzyl-1- (3-chlorobenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 68 mg (1.80 mmol) implemented sodium borohydride. The title compound is obtained

as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.29, FD-MS: M⁺ = 470.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (4-chlorobenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 35, 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 72 μl (0.515 mmol) triethylamine and 60 μl (0.468 mmol) 3-chlorobenzoyl chloride converted to the product. TLC methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.71, FD-MS: M⁺ = 566.

Example 37: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -N- (3-carboxamido-propionyl) -4-piperidinamine

als weisse feste Substanz. DC: Methylenchlorid/Methanol/ conc. Ammoniak (700:50:1) R_f=0.23, FD-MS: M⁺= 602, 604.
Als Nebenprodukt wird aus der Chromatographie (2R*,4S*)-2-Benzyl-1-(3,5-dichlorbenzoyl)-N-(4-chinolylmethyl)-N-(3-N-cyclohexyl-carbamido-propionyl)-4-piperidinamin erhalten. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.40, FD-MS: M⁺= 684, 686.92 mg (0.99 mmol) of 1-hydroxybenzotriazole and 138 mg (0.899 mmol) of N, N′-dicyclohexylcarbodiimide are added to a solution of 181 mg (0.299 mmol) (2R *, 4S *) - 2-benzyl-1- (3 , 5-dichlorobenzoyl) -N- (4-quinolylmethyl) -N- (3-carboxypropionyl) -4-piperidinamine in 2 ml of tetrahydrofuran. After stirring for half an hour at room temperature, 2.1 ml (15 mmol) of a 7 M solution of ammonia in ethanol are added and the mixture is stirred for 36 hours at room temperature. It is concentrated on a rotary evaporator, the residue is suspended in methylene chloride / ether (1: 1) and the white suspension is filtered off. The filtrate is concentrated on a rotary evaporator and the yellow oil with methylene chloride / methanol / conc. Ammonia (1000: 50: 1) chromatographed on silica gel. The title compound is obtained

as a white solid substance. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.23, FD-MS: M⁺ = 602, 604.
As a by-product from the chromatography (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -N- (3-N-cyclohexyl-carbamido-propionyl) - Obtained 4-piperidinamine. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.40, FD-MS: M⁺ = 684, 686.

Example 38: (2R, 4S) -2-benzyl-1- (3,5-bis (trifluoromethyl) benzoyl) -N- (4-quinolylmethyl) -4-piperidinamine

(3.5 g, 79%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.21, FD-MS: M⁺= 571, [α]_D = + 0.7 (c=1, MeOH), IR: 1635 cm⁻¹.Analogously to Example 2g, 3.35 g (7.78 mmol) (2R, 4S) -2-benzyl-1- (3,5-bis- (trifluoromethyl) -benzoyl) -4-piperidinamine with 1.34 g (8.56 mmol) quinoline-4- carboxaldehyde and 1.3 g of magnesium sulfate in 30 ml of toluene and then reduced with 324 mg (8.56 mmol) of sodium borohydride in 25 ml of methanol. The title compound is obtained

(3.5 g, 79%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.21, FD-MS: M⁺ = 571, [α] _D = + 0.7 (c = 1, MeOH), IR: 1635 cm⁻¹.

The starting connection for this is established as follows:

a) (2R, 4R) -2-benzyl-1- t-butyloxycarbonyl-4-hydroxy-piperidine

To a solution of 26.9 g (92.3 mmol) of (2R *, 4R *) - 2-benzyl-1-t-butyloxycarbonyl-4-hydroxy-piperidine in 200 ml of pyridine at 0 ° C 24 g (111 mmol) of (-) -Camphanoyl chloride and the mixture, which becomes heterogeneous, is stirred at 0 ° C. for 2 hours and then at RT for 16 hours. After concentration on a rotary evaporator, the reaction mixture is taken up in methylene chloride, washed twice with 10% citric acid, once with water and once with brine, dried over magnesium sulfate and evaporated on a rotary evaporator.
47.8 g of the diastereomeric mixture of camphanoic acid esters are obtained as an orange oil. Diastereomer A: R _f = 0.52; Diastereomer B: R _f = 0.47. This is chromatographed on silica gel using toluene / ethyl acetate (9: 1) and the diastereomeric esters are crystallized from hexane.
Diastereomer A is obtained in white crystals (14.2 g, 33%); M.p .: 114-115 ° C and the diastereomer B in white crystals (15.3 g, 35%); M.p .: 138-139 ° C.

The solution of diastereomer B in 300 ml of methanol is mixed with 130 ml of 0.5N sodium hydroxide solution and the reaction mixture is stirred at RT for 18 hours. After concentration on a rotary evaporator, the reaction mixture is taken up in methylene chloride, washed with water and brine, dried over magnesium sulfate and evaporated on a rotary evaporator. The title compound is obtained as a yellow oil (9.3 g, 98%). TLC: toluene / ethyl acetate (7: 3) R _f = 0.34, FD-MS: M⁺ = 291, [α] _D = + 32 ° (c = 1, methanol).

b) (2R, 4R) -2-benzyl-1- t-butyloxycarbonyl-4- (O-methylsulfonyl) -hydroxypiperidine

Analogously to Example 2d to be 9.3 g (32 mmol) of (2R, 4R) -2-benzyl-1- t-butyloxycarbonyl-4-hydroxy-piperidin reacted in 10 ml of pyridine with 5 ml (63.8 mmol) of methanesulfonyl chloride. The title compound (11 g, 93%) is obtained as colorless needles. M.p .: 137 ° C, TLC: toluene / ethyl acetate (4: 1) R _f = 0.42, [α] _D = + 21 ° (c = 1, MeOH).

c) (2R, 4S) -2-benzyl-1- t-butyloxycarbonyl-4-piperidinazid

Analogously to Example 2e 10.9 g (29.6 mmol) of (2R, 4R) -2-benzyl-1- t-butyloxycarbonyl-4- (O-methylsulfonyl) -hydroxypiperidine with 1.6 g (32.6 mmol) of lithium azide in 60 ml N, N- Dimethylformamide implemented. The title compound is obtained in a mixture with 2-benzyl-N- t- butyloxycarbonyl-1,2,5,6-tetrahydropyridine (9.2 g, weight ratio according to NMR: 4.7: 1), which is not further separated. TLC: toluene / ethyl acetate (9: 1) R _f = 0.59.

d) (2R, 4S) -2-benzyl-4-piperidine azide

The mixture from Example 38c (calculated content of (2R, 4S) -2-benzyl-1- t-butyloxycarbonyl-4-piperidinazid: 7:58 g (80%)) is mixed with 36 ml of trifluoroacetic acid and stirred for 90 minutes at RT. The mixture is then concentrated on a rotary evaporator, the residue is taken up in methylene chloride and washed with 2N sodium hydroxide solution. The organic phases are dried over magnesium sulfate and evaporated to dryness. The residue is washed with methylene chloride / methanol / conc. Ammonia (1000: 50: 1) chromatographed on silica gel. The title compound (4.7 g, 92%) is obtained as a yellow oil. TLC: methylene chloride / methanol / conc. Ammonia (350: 50: 1) R _f = 0.63, IR: 2100 cm⁻¹, [α] _D = -28.8 ° (c = 1, methanol).

e) (2R, 4S) -2-benzyl-1- (3,5-bis (trifluoromethyl) benzoyl) -4-piperidine azide

Analogously to Example 4a, 2.2 g (10.2 mmol) (2R, 4S) -2-benzyl-4-piperidinazide are mixed with 2.5 g (12.2 mmol) 3,5-bis- (trifluoromethyl) -benzoic acid, 3.1 g (12.2 mmol) bis- (2-oxo-3-oxazolidinyl) phosphinic acid chloride and 3.1 ml (22.4 mmol) of triethylamine. The title compound (4.16 g, 90%) is obtained as a yellow oil. TLC: toluene / ethyl acetate (9: 1) R _f = 0.45, FD-MS: M⁺ = 456, [α] _D = + 5.1 ° (c = 1, methanol).

f) (2R, 4S) -2-benzyl-1- (3,5-bis (trifluoromethyl) benzoyl) -4-piperidinamine

Analogously to Example 2f, 4.1 g (9.0 mmol) (2R, 4S) -2-benzyl-1- (3,5-bis- (trifluoromethyl) benzoyl) -4-piperidinazide are hydrogenated with 10% Pd / C. The title compound (3.38 g, 87%) is obtained as an oil. TLC: methylene chloride / methanol / conc. Ammonia (350: 50: 1) R _f = 0.47, FD-MS: M⁺ = 430, [α] _D = - 3.0 ° (c = 1, methanol).

Example 39: (2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine

(2.2 g, 82%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.35, FD-MS: M⁺= 503, 505, [α]_D = - 19.3 (c= 1, MeOH), IR: 1635, 1595, 1565 cm⁻¹.Analogously to Example 2g, 1.95 g (5.37 mmol) (2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine with 0.93 g (5.90 mmol) quinoline-4-carboxaldehyde and 0.9 g magnesium sulfate are added 18 ml of toluene reacted and then with 223 mg (5.90 mmol) sodium borohydride reduced in 18 ml methanol. The title compound is obtained

(2.2 g, 82%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.35, FD-MS: M⁺ = 503, 505, [α] _D = - 19.3 (c = 1, MeOH), IR: 1635, 1595, 1565 cm⁻¹.

The starting connection for this is established as follows:

a) (2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidine azide

The solution of 2.8 g (13.3 mmol) 3 is added dropwise at 0 ° C. to the solution of 2.4 g (11.1 mmol) (2R, 4S) -2-benzyl-4-piperidinazide and 2.2 ml (15.5 mmol) triethylamine in 35 ml methylene chloride , 5-dichlorobenzoyl chloride. After stirring at 0 ° C. for 18 hours, the mixture is concentrated on a rotary evaporator and the yellow oil is partitioned between methylene chloride and water. The organic phases are washed with brine, dried over magnesium sulfate and evaporated to dryness. The oil obtained is chromatographed on silica gel using toluene / ethyl acetate (9: 1). The title compound (4.04 g, 94%) is obtained as a semi-crystalline mass. TLC: toluene / ethyl acetate (9: 1) R _f = 0.51; FD-MS: M⁺ = 388, 390; [α] _D = + 33.4 ° (c = 1, MeOH).

b) (2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine

Analogously to Example 2f, 4.02 g (10.3 mmol) of (2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidine azide are hydrogenated with 10% Pd / C. The title compound (1.97 g, 52%) is obtained as an oil. TLC: methylene chloride / methanol / conc. Ammonia (350: 50: 1) R _f = 0.40, FD-MS: M⁺ = 362, 364; IR: 3660, 3360, 1630 cm⁻¹; [α] _D = + 22.7 ° (c = 1, methanol).

Example 40: (2R *, 4S *) - 2-benzyl-1- (2,4-dichlorobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine

(157 mg, 96%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.45, FD-MS: M⁺= 503,505.The solution of 195 mg (0.325 mmol) (2R *, 4S *) - 2-benzyl-1- (2,4-dichlorobenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine and 26 mg ( 0.649 mmol) of sodium hydroxide in 2 ml of methanol and 2 ml of tetrahydrofuran are allowed to stir at 0 ° C. for 18 hours. The reaction mixture is then concentrated, taken up in methylene chloride and washed with water and brine. The organic phases are dried over magnesium sulfate and evaporated to dryness. The yellow oil is washed with methylene chloride / methanol / conc. Ammonia (800: 50: 1) chromatographed on silica gel. The title compound is obtained

(157 mg, 96%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.45, FD-MS: M⁺ = 503.505.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-Benzyl-1- (2,4-dichlorobenzoyl) -N- (4-quinolylmethyl-N-trifluoroacetyl-4-piperidinamine

Analogously to Example 35a, 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 91 μl (0.655 mmol) triethylamine and 78 μl (0.561 mmol) 2,4-dichlorobenzoyl chloride converted to the title compound (240 mg, 86%). TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.57, FD-MS: M⁺ = 599, 601.

Example 41: (2R *, 4S *) - 2-benzyl-1- (phenylacetyl) -N- (4-quinolylmethyl) -4-piperidinamine

(73 mg, 46%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.43, FD-MS: M⁺= 449.Analogously to Example 40, 192 mg (0.352 mmol) (2R *, 4S *) - 2-benzyl-1- (2-phenylacetyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 141 ul (0.704 mmol) 5N sodium hydroxide solution in 1 ml of tetrahydrofuran and 1 ml of methanol. The title compound is obtained

(73 mg, 46%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.43, FD-MS: M⁺ = 449.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (phenylacetyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 35a, 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 72 μl (0.515 mmol) triethylamine and 62 μl (0.468 mmol) of phenylacetyl chloride converted to the title compound (208 mg, 81%). TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.54, FD-MS: M⁺ = 545.

Example 42: (2R *, 4S *) - 2-benzyl-1- (2,6-dichlorobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine

(56 mg, 48%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.50, FD-MS: M⁺= 503, 505.Analogously to Example 40, 138 mg (0.230 mmol) (2R *, 4S *) - 2-benzyl-1- (2,6-dichlorobenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 18.4 mg (0.460 mmol) sodium hydroxide in 1.5 ml of tetrahydrofuran and 1.5 ml of methanol. The title compound is obtained

(56 mg, 48%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.50, FD-MS: M⁺ = 503, 505.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (2,6-dichlorobenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 35a, 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 91 μl (0.655 mmol) triethylamine and 80 μl (0.561 mmol) 2,6-dichlorobenzoyl chloride converted to the title compound (158 mg, 56%). TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.62, FD-MS: M⁺ = 599, 601.

Example 43: (2R *, 4S *) - 2-benzyl-1- (3,5-dibromobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine.

(0.094 g, 66%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.23, FD-MS: M⁺= 591, 593, 595Analogously to Example 2, 0.166 g (0.241 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dibromobenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 0.037 g (0.96 mmol) sodium borohydride reacted. The title compound is obtained

(0.094 g, 66%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.23, FD-MS: M⁺ = 591, 593, 595

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (3,5-dibromobenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 2a, 197 mg (0.70 mmol) of 3,5-dibromobenzoic acid (produced according to: J. Organometallic Chem. 215 , 281 (1981)) are firstly treated with 2 ml (27 mmol) of thionyl chloride and then with 200 mg (0.468 mmol) ( 2R *, 4S *) - 2-Benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine and 130 µl (0.936 mmol) triethylamine converted to the title compound (168 mg, 52%). TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.60, FD-MS: M⁺ = 687, 689, 691.

Example 44: (2R *, 4S *) - 2-benzyl-1- (9-fluorenoyl) -N- (4-quinolylmethyl) -4-piperidinamine .

(0.155 g, 79%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.36, FD-MS: M⁺= 523.Analogously to Example 2, 0.238 g (0.384 mmol) (2R *, 4S *) - 2-benzyl-1- (9-fluorenoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 0.066 g (1.54 mmol) implemented sodium borohydride. The title compound is obtained

(0.155 g, 79%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.36, FD-MS: M⁺ = 523.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (9-fluorenoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 4a, 200 mg (0.467 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 78 mg (0.562 mmol) 9-fluorenecarboxylic acid, 143 mg (0.561 mmol) of bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride and 144 μl (1.03 mmol) of triethylamine. The title compound (241 mg, 82%) is obtained as an oil. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.58, FD-MS: M⁺ = 619.

Example 45: (2R *, 4S *) - 2-benzyl-1- (3-toluoyl) -N- (4-quinolylmethyl) -4-piperidinamine .

(0.172 g, 83%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.27, FD-MS: M⁺= 449.Analogously to Example 2, 0.251 g (0.460 mmol) (2R *, 4S *) - 2-benzyl-1- (3-toluoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 0.070 g (1.84 mmol) implemented sodium borohydride. The title compound is obtained

(0.172 g, 83%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.27, FD-MS: M⁺ = 449.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (3-toluoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 2a, 96 mg (0.70 mmol) of m-toluic acid are first treated with 2 ml (27 mmol) of thionyl chloride and then with 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine and 118 ul (0.842 mmol) of triethylamine converted to the title compound (251 mg, 98%). TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.51, FD-MS: M⁺ = 545.

Example 46: (2R *, 4S *) - 2-benzyl-1- (3-bromobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine .

(0.212 g, 93%) als Öl. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.29, FD-MS: M⁺= 513, 515.Analogously to Example 2, 0.271 g (0.444 mmol) (2R *, 4S *) - 2-benzyl-1- (3-bromobenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 0.067 g (1.78 mmol) implemented sodium borohydride. The title compound is obtained

(0.212 g, 93%) as an oil. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.29, FD-MS: M⁺ = 513, 515.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (3-bromobenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 2a, 141 mg (0.70 mmol) of m-bromobenzoic acid are first treated with 2 ml (27 mmol) of thionyl chloride and then with 200 mg (0.468 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine and 118 ul (0.842 mmol) triethylamine converted to the title compound (271 mg, 95%). TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.71, FD-MS: M⁺ = 609, 611.

Example 47: (2R *, 4S *) - 2-benzyl-1- (3,5-dihydroxybenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine .

(0.023 g, 29%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (350:50:1) R_f=0.57, FD-MS: M⁺= 467.Analogously to Example 2, 0.097 g (0.172 mmol) (2R *, 4S *) - 2-benzyl-1 - (3,5-dihydroxybenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 0.026 g (0.688 mmol) sodium borohydride reacted. The title compound is obtained

(0.023 g, 29%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (350: 50: 1) R _f = 0.57, FD-MS: M⁺ = 467.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (3,5-dihydroxybenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 4a, 200 mg (0.467 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 87 mg (0.562 mmol) 3,5-dihydroxybenzoic acid, 143 mg (0.561 mmol)
Bis- (2-oxo-3-oxazolidinyl) phosphinic acid chloride and 144 ul (1.03 mmol) of triethylamine. The title compound (99 mg, 38%) is obtained as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.41, FD-MS: M⁺ = 563.

Example 48: (2R *, 4S *) - 2-benzyl-1- (3-cyanbenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine .

(0.157 g, 62%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.51, FD-MS: M⁺= 460.Analogously to Example 2, 0.248 g (0.446 mmol) (2R *, 4S *) - 2-benzyl-1- (3-cyanbenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 0.068 g (1.78 mmol) implemented sodium borohydride. The title compound is obtained

(0.157 g, 62%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.51, FD-MS: M⁺ = 460.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-Benzyl-1- (3-cyanbenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 4a, 200 mg (0.467 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 69 mg (0.514 mmol) 3-cyanobenzoic acid, 143 mg (0.561 mmol) of bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride and 144 μl (1.03 mmol) of triethylamine. The title compound (250 mg, 96%) is obtained as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.53, FD-MS: M⁺ = 556.

Example 49: (2R *, 4S *) - 2-benzyl-1- (2-chlorobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine .

(0.109 g, 80%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.33, MS: M⁺= 469, 471; IR: 3680, 1640, 1605, 1580 cm⁻¹.Analogously to Example 2, 0.165 g (0.291 mmol) (2R *, 4S *) - 2-benzyl-1- (2-chlorobenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 0.044 g (1.16 mmol) implemented sodium borohydride. The title compound is obtained

(0.109 g, 80%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.33, MS: M⁺ = 469, 471; IR: 3680, 1640, 1605, 1580 cm -1.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (2-chlorobenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 4a, 200 mg (0.467 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 88 mg (0.560 mmol) 2-chlorobenzoic acid, 143 mg (0.561 mmol) of bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride and 144 μl (1.03 mmol) of triethylamine. The title compound (179 mg, 68%) is obtained as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (2000: 50: 1) R _f = 0.42, FD-MS: M⁺ = 565, 567.

Example 50: (2R *, 4S *) - 2-benzyl-1- (4-chlorobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine .

(0.136 g, 81%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.17, FD-MS: M⁺= 469, 471; IR: 3675, 1625, 1595, 1570 cm⁻¹.Analogously to Example 2, 0.202 g (0.291 mmol) (2R *, 4S *) - 2-benzyl-1- (4-chlorobenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 0.054 g (1.43 mmol) implemented sodium borohydride. The title compound is obtained

(0.136 g, 81%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.17, FD-MS: M⁺ = 469, 471; IR: 3675, 1625, 1595, 1570 cm -1.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (4-chlorobenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 4a, 200 mg (0.467 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 88 mg (0.560 mmol) 4-chlorobenzoic acid, 143 mg (0.561 mmol) of bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride and 144 μl (1.03 mmol) of triethylamine. The title compound (210 mg, 80%) is obtained as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.44, FD-MS: M⁺ = 565, 567.

Example 51: (2R *, 4S *) - 2-benzyl-1- (9-fluorenyl) -N- (4-quinolylmethyl) -4-piperidinamine

(49 mg, 45%) als weissen Schaum. DC: Toluol/Ethylacetat (1:1) R_f=0.26; FD-MS: M⁺=495.Analogously to Example 40, 130 mg (0.219 mmol) (2R *, 4S *) - 2-benzyl-1- (9-fluorenyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 500 μl (0.500 mmol) 1N sodium hydroxide solution in 1 ml of tetrahydrofuran and 1 ml of methanol. The title compound is obtained

(49 mg, 45%) as a white foam. TLC: toluene / ethyl acetate (1: 1) R _f = 0.26; FD-MS: M⁺ = 495.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (9-fluorenyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 25a, 200 mg (0.467 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 138 mg (0.561 mmol) 9-bromofluorene and 155 mg (1.12 mmol) potassium carbonate reacted in 2.5 ml acetone. The title compound (131 mg, 47%) is obtained as an oil. TLC: toluene / ethyl acetate (1: 1) R _f = 0.43; FD-MS: M⁺ = 591.

Example 52: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -N-methyl-4-piperidinamine

(20 mg, 13%) als weissen Schaum. DC: Toluol/Ethylacetat (1:1) R_f=0.45; FD-MS: M⁺=517, 519.For the solution of 150 mg (0.297 mmol) (2S *, 4R *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine in 2 ml 1,2-dimethoxyethane 13.4 mg (0.446 mmol) of an 80% suspension of sodium hydride in mineral oil (suspended with hexane and decanted) are added in one portion at 0 ° C. After 10 minutes at 0 ° C., the mixture is stirred at RT for 30 minutes, cooled again to 0 ° C. and 22 μl (0.357 mmol) of methyl iodide are added. The mixture is then stirred at RT for 96 hours. The solvent is removed on a rotary evaporator and the residue is chromatographed on silica gel using toluene / ethyl acetate (1: 1). The title compound is obtained

(20 mg, 13%) as a white foam. TLC: toluene / ethyl acetate (1: 1) R _f = 0.45; FD-MS: M⁺ = 517, 519.

Example 53: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -N-cyclohexylcarbamoyl-4-piperidinamine

als weisse Kristalle (165 mg, 66%) vom Schmelzpunkt 229°C (Zersetzung). DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.44, FD-MS: M⁺= 628, 630.Analogously to Example 16a, 200 mg (0.396 mmol) (2S *, 4R *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine are mixed with 66 µl (0.515 mmol) Cyclohexyl isocyanate implemented. The title compound is obtained

as white crystals (165 mg, 66%) with a melting point of 229 ° C (decomposition). TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.44, FD-MS: M⁺ = 628, 630.

Example 54: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -N-phenylcarbamoyl-4-piperidinamine

als festen Rückstand (129 mg, 52%). DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.42, FD-MS: M⁺= 622, 624.Analogously to Example 16a, 200 mg (0.396 mmol) (2S *, 4R *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine with 45 mg (0.377 mmol) Phenyl isocyanate implemented. The title compound is obtained

as a solid residue (129 mg, 52%). TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.42, FD-MS: M⁺ = 622, 624.

Example 55: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (2-phenylethyl) -4-piperidinamine

(0.101 g, 94%) als Öl. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.34, FD-MS: M⁺= 466, 468.Analogously to Example 2, 0.130 g (0.231 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (2-phenylethyl) -N-trifluoroacetyl-4-piperidinamine with 0.035 g (0.923 mmol) sodium borohydride reacted. The title compound is obtained

(0.101 g, 94%) as an oil. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.34, FD-MS: M⁺ = 466, 468.

The starting connection for this is established as follows:

a) (2R *, 4S *) - 2-benzyl-1- t- butyloxycarbonyl-N- (2-phenylethyl) -4-piperidinamine

Analogously to Example 11a 1 g (3:44 mmol) of (2R *, 4S *) - 2-benzyl-1-t-butyloxycarbonyl-4-piperidinamine with 1 ml (4:48 mmoles) of phenylacetaldehyde, 0.433 g (6.89 mmol) of sodium cyanoborohydride, 0.791 g ( 9.64 mmol) sodium acetate and 434 ul acetic acid to the title compound (805 mg, 60%). TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.35, FD-MS: M⁺ = 394.

b) (2R *, 4S *) - 2-benzyl-1-t-butyloxycarbonyl-N- (2-phenylethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 2h 618 mg (1:57 mmol) of (2R *, 4S *) - 2-benzyl-1-t-butyloxycarbonyl-N- (4-quinolylmethyl) -4-piperidinamine with 240 .mu.l (1.72 mmol) of trifluoroacetic anhydride and 284 .mu.l (2.04 mmol) triethylamine reacted. The title compound is obtained as a white foam (572 mg, 75%). TLC: toluene / ethyl acetate (9: 1) R _f = 0.47, FD-MS: (M + H) ⁺ = 491.

c) (2R *, 4S *) - 2-benzyl-N- (2-phenylethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 38d, 615 mg (1.25 mmol) of (2R *, 4S *) - 2-benzyl-1-t-butyloxycarbonyl-N- (2-phenylethyl) -N-trifluoroacetyl-4-piperidinamine with 1.9 ml (25 mmol) Trifluoroacetic acid implemented. The title compound is obtained as an oil (308 mg, 63%). TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.63, FD-MS: M⁺ = 390.

d) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (2-phenylethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 2a, 189 mg (0.992 mmol) of 3,5-dichlorobenzoic acid are first treated with 0.108 ml (1.49 mmol) of thionyl chloride and then with 155 mg (0.397 mmol) (2R *, 4S *) - 2-benzyl-N- (2- phenylethyl) -N-trifluoroacetyl-4-piperidinamine and 166 ul (1.19 mmol) of triethylamine converted to the title compound (135 mg, 60%). TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.70, FD-MS: M⁺ = 562, 564.

Example 56: (2R *, 4S *) - 2-benzyl-1- (3,5-bis (trifluoromethyl) benzoyl) -N- (2-phenylethyl) -4-piperidinamine

(0.123 g, 76%) als Öl. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.22, FD-MS: M⁺= 534, IR: 1630 cm⁻¹.Analogously to Example 2, 0.190 g (0.301 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-bis- (trifluoromethyl) -benzoyl) -N- (2-phenylethyl) -N-trifluoroacetyl- 4-piperidinamine reacted with 0.046 g (1.21 mmol) sodium borohydride. The title compound is obtained

(0.123 g, 76%) as an oil. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.22, FD-MS: M⁺ = 534, IR: 1630 cm⁻¹.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-Benzyl-1- (3,5-bis (trifluoromethyl) benzoyl) -N- (2-phenylethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 4a, 150 mg (0.384 mmol) (2R *, 4S *) - 2-benzyl-N- (2-phenylethyl) -N-trifluoroacetyl-4-piperidinamine with 93 mg (0.461 mmol) 3,5-bis- (trifluoromethyl) benzoic acid, 117 mg (0.461 mmol) of bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride and 118 μl (0.845 mmol) of triethylamine. The title compound (191 mg, 79%) is obtained as an oil. TLC: methylene chloride / methanol / conc. Ammonia (2000: 50: 1) R _f = 0.79, FD-MS: M⁺ = 630.

Example 57: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (2-naphthoyl) -4-piperidinamine

umgesetzt (272 mg, 96%). DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.73, FD-MS: (M+H)⁺= 516, 518, 520, IR: 3420, 1625 cm⁻¹.Analogously to Example 2a, 142 mg (0.825 mmol) of 2-naphthoic acid are first treated with 2 ml (27 mmol) of thionyl chloride and then with 200 mg (0.550 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5- dichlorobenzoyl) -4-piperidinamine and 138 µl (0.991 mmol) triethylamine to give the title compound

implemented (272 mg, 96%). TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.73, FD-MS: (M + H) ⁺ = 516, 518, 520, IR: 3420, 1625 cm⁻¹.

The starting connection for this is established as follows:

a) (2R *, 4S *) - 2-benzyl-4-piperidine azide

Analogously to Example 38d, 15 g (38.3 mmol) of the mixture from Example 2e are reacted with 70 ml of trifluoroacetic acid. The title compound (7.15 g, 87%) is obtained as an oil. TLC: methylene chloride / methanol / conc. Ammonia (350: 50: 1) R _f = 0.57, FD-MS: M⁺ = 216.

b) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidine azide

Analogously to Example 2a, 6.62 g (34.7 mmol) of 3,5-dichlorobenzoic acid are first mixed with 3.78 ml (52.0 mmol) of thionyl chloride and then with 3.0 g (13.9 mmol) (2R *, 4S *) - 2-benzyl-4-piperidinazide and 5.8 ml (41.6 mmol) of triethylamine converted to the title compound (5.18 g, 96%). TLC: methylene chloride / methanol / conc. Ammonia (2000: 50: 1) R _f = 0.77, DCI-MS: (M + H) ⁺ = 389, 391.

c) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine

Analogously to Example 2f, 11.0 g (28.3 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidine azide are hydrogenated with 10% Pd / C. The title compound (8.76 g, 85%) is obtained as an oil. TLC: methylene chloride / methanol / conc. Ammonia (350: 50: 1) R _f = 0.40, FD-MS: M⁺ = 362, 364.

Example 58: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl-N) - (3,5-dimethylbenzoyl) -4-piperidinamine

umgesetzt (200 mg, 73%). DC: Methylenchlorid/Methanol/conc. Ammoniak (2000:50:1) R_f=0.61, FD-MS: (M+H)⁺= 494, 496; IR: 3420, 1625 cm⁻¹Analogously to Example 2a, 124 mg (0.825 mmol) of 3,5-dimethylbenzoic acid are first treated with 2 ml (27 mmol) of thionyl chloride and then with 200 mg (0.550 mmol) (2R *, 4S *) - 2-benzyl-1- (3, 5-dichlorobenzoyl) -4-piperidinamine and 138 µl (0.991 mmol) triethylamine to the product

implemented (200 mg, 73%). TLC: methylene chloride / methanol / conc. Ammonia (2000: 50: 1) R _f = 0.61, FD-MS: (M + H) ⁺ = 494, 496; IR: 3420, 1625 cm -1

Example 59: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylcarbonyl) -4-piperidinamine

(278 mg, 97%) als Öl. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.45, FD-MS: M⁺= 517, 519; IR: 3395, 1755, 1620 cm⁻¹.Analogously to Example 4a, 200 mg (0.550 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine with 105 mg (0.660 mmol) quinoline-4-carboxylic acid, 168 mg (0.661 mmol) of bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride and 169 μl (1.21 mmol) of triethylamine. The title compound is obtained

(278 mg, 97%) as an oil. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.45, FD-MS: M⁺ = 517, 519; IR: 3395, 1755, 1620 cm -1.

Example 60: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (3-indolylcarbonyl) -4-piperidinamine

(92 mg, 33%) als Öl. DC: Methylenchlorid/Methanol/conc. Ammoniak (350:50:1) R_f=0.61, FD-MS: M⁺= 505, 507; IR: 3450, 3260, 1770, 1635 cm⁻¹.Analogously to Example 4a, 200 mg (0.550 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine with 106 mg (0.661 mmol) indole-3-carboxylic acid, 168 mg (0.661 mmol) of bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride and 169 μl (1.21 mmol) of triethylamine. The title compound is obtained

(92 mg, 33%) as an oil. TLC: methylene chloride / methanol / conc. Ammonia (350: 50: 1) R _f = 0.61, FD-MS: M⁺ = 505, 507; IR: 3450, 3260, 1770, 1635 cm -1.

Example 61: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (2-indolylcarbonyl) -4-piperidinamine

(89 mg, 32%) als weisse Kristalle vom Schmelzpunkt 254°C. DC: Methylenchlorid/Methanol/conc. Ammoniak (2000:50:1) R_f=0.56, FD-MS: M⁺= 505, 507; IR: 3430, 3290, 1625 cm⁻¹.Analogously to Example 4a, 200 mg (0.550 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine with 106 mg (0.661 mmol) indole-2-carboxylic acid, 168 mg (0.661 mmol) of bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride and 169 μl (1.21 mmol) of triethylamine. The title compound is obtained

(89 mg, 32%) as white crystals with a melting point of 254 ° C. TLC: methylene chloride / methanol / conc. Ammonia (2000: 50: 1) R _f = 0.56, FD-MS: M⁺ = 505, 507; IR: 3430, 3290, 1625 cm -1.

Example 62: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (5-methoxy-2-indolylcarbonyl) -4-piperidinamine

Analogously to Example 4a, 200 mg (0.550 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine are mixed with 126 mg (0.661 mmol) 5-methoxy-indole-2- carboxylic acid, 168 mg (0.661 mmol) of bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride and 169 μl (1.21 mmol) of triethylamine. The title compound is obtained

(118 mg, 41%) as white crystals with a melting point of 251 ° C. TLC: methylene chloride / methanol / conc. Ammonia (2000: 50: 1) R _f = 0.81, FD-MS: M⁺ = 535, 537; IR: 3440, 3280, 1625 cm -1.

Example 63: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzyl) -N- (1-naphthoyl) -4-piperidinamine

(208 mg, 97%) als Öl. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.85, FD-MS: M⁺= 516, 518; IR: 3680, 3400, 1620 cm⁻¹.Analogously to Example 39a, 150 mg (0.431 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine are mixed with 75 μl (0.495 mmol) 1-naphthoyl chloride and 81 μl (0.578 mmol) of triethylamine. The title compound is obtained

(208 mg, 97%) as an oil. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.85, FD-MS: M⁺ = 516, 518; IR: 3680, 3400, 1620 cm -1.

Example 64: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (phenylacetyl) -4-piperidinamine

(127 mg, 48%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.56, FD-MS: M⁺= 480, 482; IR: 3660, 3405, 1665, 1630 cm⁻¹.Analogously to Example 39a, 200 mg (0.551 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine are mixed with 88 µl (0.661 mmol) phenylacetyl chloride and 108 µl (0.771 mmol) Triethylamine implemented. The title compound is obtained

(127 mg, 48%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.56, FD-MS: M⁺ = 480, 482; IR: 3660, 3405, 1665, 1630 cm -1.

Example 65: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (2-methoxybenzyl) -4-piperidinamine

(170 mg, 64%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (700:50:1) R_f=0.66, FD-MS: M⁺= 482, 482. IR: 1620 cm⁻¹.Analogously to Example 2g, 200 mg (0.551 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine are mixed with 75 mg (0.551 mmol) 2-methoxybenzaldehyde and 90 mg magnesium sulfate 2 ml of toluene reacted and then reduced with 22 mg (0.584 mmol) of sodium borohydride in 2 ml of methanol. The title compound is obtained

(170 mg, 64%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (700: 50: 1) R _f = 0.66, FD-MS: M⁺ = 482, 482. IR: 1620 cm⁻¹.

Example 66: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (3- (N-acetyl) indolylmethyl) -4-piperidinamine

(30 mg, 10%) als Öl. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.57, FD-MS: M⁺= 533, 535. IR: 1720, 1680, 1635 cm⁻¹.Analogously to Example 2g, 200 mg (0.551 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine with 113 mg (0.606 mmol) N-acetylindol-3-carboxaldehyde and 90 mg of magnesium sulfate are reacted in 2 ml of toluene and then reduced with 31 mg (0.826 mmol) of sodium borohydride in 3 ml of methanol. The title compound is obtained

(30 mg, 10%) as an oil. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.57, FD-MS: M⁺ = 533, 535. IR: 1720, 1680, 1635 cm⁻¹.

Example 67: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (2-benzo [b] furanylmethyl) -4-piperidinamine

(150 mg, 55%) als Öl. DC: Methylenchlorid/Methanol/conc. Ammoniak (2000:50:1) R_f=0.18, FD-MS: M⁺= 492, 494. IR: 1630 cm⁻¹.Analogously to Example 2g, 200 mg (0.551 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine with 97 mg (0.661 mmol) benzofuran-2-carboxaldehyde and 90 mg Magnesium sulfate reacted in 2 ml of toluene and then reduced with 22 mg (0.584 mmol) of sodium borohydride in 2 ml of methanol. The title compound is obtained

(150 mg, 55%) as an oil. TLC: methylene chloride / methanol / conc. Ammonia (2000: 50: 1) R _f = 0.18, FD-MS: M⁺ = 492, 494. IR: 1630 cm⁻¹.

Example 68: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N - [(3-methylbenzo [b] thiophene-2-ylmethyl] -4-piperidinamine

(75 mg, 25%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (2000:50:1) R_f=0.38, FD-MS: M⁺= 522, 524. IR: 1630 cm⁻¹.Analogously to Example 2g, 200 mg (0.551 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine are mixed with 116 mg (0.661 mmol) 3-methylbenzo [b] thiophene- 2-carboxaldehyde and 90 mg of magnesium sulfate in 2 ml of toluene and then reduced with 22 mg (0.584 mmol) of sodium borohydride in 2 ml of methanol. The title compound is obtained

(75 mg, 25%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (2000: 50: 1) R _f = 0.38, FD-MS: M⁺ = 522, 524. IR: 1630 cm⁻¹.

Example 69: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (5-methoxyindol-3-ylmethyl) -4-piperidinamine

(98 mg, 34%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.42, FD-MS: M⁺= 521, 523. IR: 3460, 1630 cm⁻¹.Analogously to Example 2g, 200 mg (0.551 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine with 116 mg (0.661 mmol) 5-methoxyindole-3-carboxaldehyde and 90 mg of magnesium sulfate are reacted in 2 ml of toluene and then reduced with 22 mg (0.584 mmol) of sodium borohydride in 2 ml of methanol. The title compound is obtained

(98 mg, 34%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.42, FD-MS: M⁺ = 521, 523. IR: 3460, 1630 cm⁻¹.

Example 70: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (3-indolylmethyl) -4-piperidinamine

(75 mg, 28%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (400:50:1) R_f=0.49, FD-MS: M⁺= 491, 493. IR: 3460, 1630 cm⁻¹.Analogously to Example 2g, 200 mg (0.551 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine with 80 mg (0.551 mmol) indole-3-carboxaldehyde and 90 mg Magnesium sulfate reacted in 2 ml of toluene and then reduced with 22 mg (0.584 mmol) of sodium borohydride in 2 ml of methanol. The title compound is obtained

(75 mg, 28%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (400: 50: 1) R _f = 0.49, FD-MS: M⁺ = 491, 493. IR: 3460, 1630 cm⁻¹.

Example 71: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N-phenylcarbamoyl-4-piperidinamine

als weissen Schaum (160 mg, 60%). DC: Toluol/Ethylacetat (1:1) R_f=0.40, FD-MS: M⁺= 481, 483; IR: 1600 - 1690 cm⁻¹.Analogously to Example 16a, 200 mg (0.551 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine are reacted with 85 mg (0.716 mmol) phenyl isocyanate. The title compound is obtained

as a white foam (160 mg, 60%). TLC: toluene / ethyl acetate (1: 1) R _f = 0.40, FD-MS: M⁺ = 481, 483; IR: 1600 - 1690 cm -1.

Example 72: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N-diphenylmethyl-4-piperidinamine

als weissen Schaum (120 mg, 41%). DC: Toluol/Ethylacetat (7:3) R_f=0.79, FD-MS: M⁺= 528, 530; IR: 1630 cm⁻¹.The solution of 200 mg (0.551 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine and 110 mg (0.606 mmol) benzophenone in 5 ml toluene is used for 18 hours Held backflow. The mixture is then concentrated on a rotary evaporator, the reaction mixture is dissolved in 3 ml of methanol and 69 mg (1.10 mmol) of sodium cyanoborohydride are added at RT. The reaction mixture is adjusted to pH = 5 with 80 μl of acetic acid and stirred at RT for 68 hours. The title compound is obtained

as a white foam (120 mg, 41%). TLC: toluene / ethyl acetate (7: 3) R _f = 0.79, FD-MS: M⁺ = 528, 530; IR: 1630 cm⁻¹.

Example 73: (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (3,4-dihydro-2H-1-benzopyran-2-carbonyl) -4-piperidinamine

als weissen Schaum (69 mg, 24%). DC: Toluol/Ethylacetat (1:1) R_f=0.56, FD-MS: M⁺= 522, 524; IR: 3410, 1675, 1630 cm⁻¹.125 mg (0.606 mmol) of N, N′-dicyclohexylcarbodiimide are added to the solution of 108 mg (0.606 mmol) of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid in 3 ml of tetrahydrofuran at 0 ° C, and the reaction mixture is stirred one hour and adds 177 µl (1.27 mmol) triethylamine and 200 mg (0.551 mmol) (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -4-piperidinamine. The mixture is allowed to warm to RT and stirred at this temperature for 16 hours. It is concentrated on a rotary evaporator, the residue is suspended in methylene chloride / ether (1: 1) and the white suspension is filtered off. After concentration on a rotary evaporator, the reaction mixture is taken up in methylene chloride, washed twice with 10% citric acid, once with water, once with 2N sodium hydroxide solution and once with brine, dried over magnesium sulfate and evaporated on a rotary evaporator. The yellow oil is chromatographed on silica gel using toluene / ethyl acetate (7: 3). The diastereomer mixture of the title compound is obtained

as a white foam (69 mg, 24%). TLC: toluene / ethyl acetate (1: 1) R _f = 0.56, FD-MS: M⁺ = 522, 524; IR: 3410, 1675, 1630 cm -1.

Example 74: (2R *, 4S *) - 2-benzyl-1- (4-methoxybenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine

(0.100 g, 69%) als weissen Schaum. DC: Methylenchlorid/Methanol/conc. Ammoniak (1000:50:1) R_f=0.21, FD-MS: M⁺= 465; IR: 1620 cm⁻¹.Analogously to Example 2, 0.175 g (0.321 mmol) (2R *, 4S *) - 2-benzyl-1- (4-methoxybenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine with 0.047 g (1.25 mmol) implemented sodium borohydride. The title compound is obtained

(0.100 g, 69%) as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.21, FD-MS: M⁺ = 465; IR: 1620 cm⁻¹.

The starting connection for this is established as follows:

(2R *, 4S *) - 2-benzyl-1- (4-methoxybenzoyl) -N- (4-quinolylmethyl) -N-trifluoroacetyl-4-piperidinamine

Analogously to Example 4a, 200 mg (0.467 mmol) (2R *, 4S *) - 2-benzyl-N- (4-quinolylmethyl) -N-trifluoroacetyl-1-piperidinamine with 85 mg (0.562 mmol) p-anisic acid, 143 mg (0.561 mmol) of bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride and 91 μl (0.655 mmol) of triethylamine. The title compound (170 mg, 65%) is obtained as a white foam. TLC: methylene chloride / methanol / conc. Ammonia (1000: 50: 1) R _f = 0.37, FD-MS: M⁺ = 561.

Example 75 :

The following can also be prepared in an analogous manner to that described in Examples 1 to 74:
(2R *, 4S *) - 2-benzyl-1- (3,5-dimethylbenzoyl) -N-benzyl-N-carbamoyl-4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-phenylpropyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-phenylpropyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-methoxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-methoxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-methoxyphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-methoxyphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-methoxyphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-methoxyphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-trifluoromethylbenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-trifluoromethylbenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-trifluoromethylphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-trifluoromethylphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-trifluoromethylphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-trifluoromethylphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-trifluoromethylbenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-trifluoromethylbenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (3-trifluoromethylphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (3-trifluoromethylphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (3-trifluoromethylphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (3-trifluoromethylphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-trifluoromethylbenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-trifluoromethylbenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (4-trifluoromethylphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (4-trifluoromethylphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (4-trifluoromethylphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (4-trifluoromethylphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,3-dimethoxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,3-dimethoxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,3-dimethoxyphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,3-dimethoxyphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,3-dimethoxyphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,3-dimethoxyphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,4-dimethoxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,4-dimethoxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,4-dimethoxyphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,4-dimethoxyphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,4-dimethoxyphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,4-dimethoxyphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,5-dimethoxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,5-dimethoxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,5-dimethoxyphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,5-dimethoxyphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,5-dimethoxyphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,5-dimethoxyphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,6-dimethoxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,6-dimethoxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,6-dimethoxyphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,6-dimethoxyphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,6-dimethoxyphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,6-dimethoxyphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,3-methylenedioxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,3-methylenedioxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,3-methylenedioxyphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,3-methylenedioxyphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,3-methylenedioxyphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,3-methylenedioxyphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,4-methylenedioxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,4-methylenedioxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,4-methylenedioxyphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,4-methylenedioxyphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,4-methylenedioxyphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,4-methylenedioxyphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (4-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine and
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine.

Example 76 : (2R, 4S) - and (2R, 4R) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine dihydrochloride

Analogously to Example 1, starting from 1.26 g (3.9 mmol) (2R, 4R / S) -2-benzyl-1- (3,5-dimethylbenzoyl) -4-piperidinamine, obtained as a mixture of about 70% (2R, 4R ) - and about 30% (2R, 4S) -diastereomers by reduction with borane dimethyl sulfide according to Example elb, and using a total of 2.26 g (14.4 mmol) of quinoline-4-carboxaldehyde a mixture of the hydrochlorides of the two diastereomeric title compounds.

TLC: methylene chloride / methanol / conc. Ammonia (90: 9: 1)
Diastereomer A (2R, 4R): R _f = 0.5, MS: M⁺ = 463
Diastereomer B (2R, 4S): R _f = 0.45, MS: M⁺ = 463, mp. 144-145 °, [α] _D = + 25 ° (c = 0.94 in ethanol)

These are dissolved in ethyl acetate and treated with ethereal HCl solution, giving the dihydrochloride of the title compound.

TLC: methylene chloride / methanol / conc. Ammonia (90: 9: 1)
Diastereomer A (2R, 4R): R _f = 0.5, mp 172-174 °, [α] _D = -55.7 ° (c = 1, ethanol)
Diastereomer B (2R, 4S): R _f = 0.45, mp. 174-176 °, [α] _D = + 18 ° (c = 1, ethanol)

Example 77 : (2S, 4R) and (2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-phenethyl) -4-piperidinamine hydrochloride

Analogously to Example 1, starting from 1.87 g (5.8 mmol) (2S, 4R / S) -2-benzyl-1- (3,5-dimethylbenzoyl) -4-piperidinamine, obtained as a mixture of about 70% (2S, 4S ) - and about 30% (2S, 4R) -diastereomers by reduction using borane dimethyl sulfide according to Example elb, and using phenylacetaldehyde, the hydrochlorides of the two diastereomeric title compounds.
TLC: methylene chloride / methanol (98: 2)
Diastereomer A (2S, 4S): R _f = 0.16, mp. 250-251 ° C, [α] _D = + 56.2 ° (c = 0.980, methanol), MS: M⁺ = 426 (free base).
Diastereomer B (2S, 4R): R _f = 0.06, mp. 250 ° C (decomposition), [α] _D = -29.7 ° (c = 0.768, methanol), MS: M⁺ = 426 (free base).

Example 78 : (2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-quinolylmethyl) -4-piperidinamine

Analogously to Example 1, starting from 511 mg (1.59 mmol) (2R, 4RS) -2-benzyl-1- (3,5-dimethylbenzoyl) -4-piperidinamine using quinoline-3-carbaldehyde, the title compound is obtained by crystallization from hexane / Ethyl acetate (1: 1) in the form of colorless crystals.

TLC: methylene chloride / methanol / conc. Ammonia (90: 9: 1)
R _f = 0.5, mp. 91-93 ° C, MS: M⁺ = 463 (free base), [α] _D = + 0.7 ° (c = 1.09, methanol)

Example 79 : (2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-quinolylmethyl) -4-piperidinamine dihydrochloride

Analogously to Example 1, the title compound is obtained starting from 541 mg (1.68 mmol) (2R, 4RS) -2-benzyl-1- (3,5-dimethylbenzoyl) -4-piperidinamine using quinoline-2-carbaldehyde.

TLC: methylene chloride / methanol / conc. Ammonia (90: 9: 1)
R _f = 0.5, decomposition point: from 110 ° C, MS: M⁺ = 463 (free base), [α] _D = + 4.8 ° (c = 1,105, methanol)

Example 80 : (2R, 4S) - and (2R, 4R) -2-benzyl-1- (3,5-dimethylbenzoyl) -N-benzyl-4-piperidinamine hydrochloride

Analogously to Example 1, starting from 0.748 g (2.32 mmol) (2R, 4R / S) -2-benzyl-1- (3,5-dimethylbenzoyl) -4-piperidinamine, obtained as a mixture of about 70% (2R, 4R ) - and about 30% (2R, 4S) -diastereomers by reduction using borane dimethyl sulfide according to Example elb, and using benzaldehyde the hydrochlorides of the two diastereomeric title compounds.

TLC: methylene chloride / methanol / conc. Ammonia (95: 4.5: 0.5)
Diastereomer A (2R, 4R): R _f = 0.45, mp. 244-246 ° C, [α] _D = -50.4 ° (c = 0.979, chloroform),
MS: M⁺ = 412 (free base).
Diastereomer B (2R, 4S): R _f = 0.33, amorphous.
[α] _D = + 7.9 ° (c = 1.0, chloroform), MS: M⁺ = 412 (free base).

Example 81 : (2S, 4R) - and (2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N-benzyl-4-piperidinamine hydrochloride

Analogously to Example 1, 4.5 g (13.95 mmol) of (2S, 4R / S) -2-benzyl-1- (3,5-dimethylbenzoyl) -4-piperidinamine are obtained, obtained as a mixture of about 70% (2S, 4S ) - and about 30% (2S, 4R) diastereomers by reduction using borane dimethyl sulfide according to Example elb, and using benzaldehyde Hydrochloride of the two diastereomeric title compounds.

TLC: methylene chloride / methanol / conc. Ammonia (95: 4.5: 0.5)
Diastereomer A (2S, 4S): R _f = 0.45, mp. 246-247 ° C, [α] _D = + 51.2 ° (c = 0.672, chloroform),
MS: M⁺ = 412 (free base).
Diastereomer B (2S, 4R): R _f = 0.33, amorphous.
[α] _D = -7.7 ° (c = 0.784, chloroform), MS: M⁺ = 412 (free base).

Example 82 : (2R , 4S) - and (2R , 4R) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-pyridylmethyl) 4-piperidinamine dihydrochloride

Analogously to Example 1, starting from 100 mg (0.279 mmol) (2R, 4R / S) -2-benzyl-1- (3,5-dimethylbenzoyl) -4-piperidinamine, obtained as a mixture of about 70% (2R, 4R) - And about 30% (2R, 4S) diastereomers by reduction using borane dimethyl sulfide according to Example elb, and using pyridine-4-carbaldehyde, the two diastereomeric title compounds.

TLC: methylene chloride / methanol / conc. Ammonia (90: 9: 1)
Diastereomer A (2R, 4R): R _f = 0.68, from 142 ° C decomposition,
[α] _D = -57.3 ° (c = 0.508, ethanol), MS: M⁺ = 413 (free base).
Diastereomer B (2R, 4S): R _f = 0.44, decomposition from 145 ° C,
[α] _D = + 23.0 ° (c = 0.300, ethanol), MS: M⁺ = 413 (free base).

Example 83 : (2R , 4S) - and (2R , 4R) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-pyridylmethyl) -4-piperidinamine dihydrochloride

Analogously to Example 1, starting from 100 mg (0.279 mmol) (2R, 4R / S) -2-benzyl-1- (3,5-dimethylbenzoyl) -4-piperidinamine, obtained as a mixture of about 70% (2R, 4R) - And about 30% (2R, 4S) diastereomers by reduction using borane dimethyl sulfide according to Example elb, and using pyridine-3-carbaldehyde, the two diastereomeric title compounds.

TLC: methylene chloride / methanol / conc. Ammonia (90: 9: 1)
Diastereomer A (2R, 4R): R _f = 0.68, from 105 ° C decomposition,
[α] _D = -52.6 ° (c = 1.06, ethanol), MS: M⁺ = 413 (free base).
Diastereomer B (2R, 4S): R _f = 0.44, from 105 ° C decomposition,
[α] _D = + 22.6 ° (c = 1.03, ethanol), MS: M⁺ = 413 (free base).

Example 84 : (2S, 4R) and (2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine

Analogously to Example 1, starting from 12.1 g (37.5 mmol) (2S, 4RS) -2-benzyl-1- (3,5-dimethylbenzoyl) -4-piperidinamine, obtained as a mixture of about 70% (2S, 4S) - and about 30% (2S, 4R) diastereomers by reduction using borane dimethyl sulfide according to Example elb, and using quinoline-4-carbaldehyde, the two diastereomeric title compounds.

TLC: methylene chloride / methanol / conc. Ammonia (90: 9: 1) diastereomer A (2S, 4R): R _f = 0.59, mp. 144-145 ° C (free base) [α] _D = -25.1 ° (c = 1.0, ethanol), MS: M⁺ = 463 (free base)

Example 85 : (2R *, 4S *, 1'R *) - N-benzyl-1- (3,5-dimethylbenzoyl) -2- (1'-hydroxy-1'-benzyl) -4-piperidinamine (diastereomer A ) and (2R *, 4R *, 1'R *) - N-benzyl-1- (3,5-dimethylbenzoyl) -2- (1'-hydroxy-1'-phenyl-methyl) -4-piperidinamine (diastereomer B)

A solution of 400 mg (1.18 mmol) (2R *, 1'R * -1- (3,5-dimethylbenzoyl) -2- (1'-hydroxy-1'-phenyl-methyl) -4-piperidone and 139 mg (1.3 mmol) benzylamine in toluene / hexane is refluxed for 18 hours with azeotropic removal of water, the reaction mixture is concentrated under reduced pressure and the remaining oil is taken up in methanol, at 0 to 5 ° with 111 mg sodium cyanoborohydride (85% in mineral oil ) and stirred for 4 hours at 25 ° C. The solvent is removed under reduced pressure and the crude product in one Mixture of ethyl acetate and 10% sodium carbonate solution added. The organic phase is separated off, dried over sodium sulfate and evaporated under reduced pressure. Chromatography on silica gel with ethyl acetate as the eluent gives the two title compounds; TLC (ethyl acetate):
Diastereomer A: R _f = 0.28; M.p. 159-160 °
Diastereomer B: R _f = 0.09; Mp 190-192 °.

The starting material can be produced as follows:

a) 1-tert-Butoxycarbonyl-4-piperidone ethylene ketal

26.1 g of ditertiary butyl dicarbonate, dissolved in 20 ml of toluene, are slowly added to a solution of 14.3 g of 4-piperidonethylene ketal in 100 ml of toluene with stirring at 0 to 5 °. The mixture is stirred at room temperature for 2 hours and then evaporated under reduced pressure and distilled under reduced pressure. 22.2 g of the title compound, b.p. 83-85 ° (0.2 Torr) are obtained. TLC (ethyl acetate / hexane; 1: 3): R _f = 0.20.

b) (2R *, 1'R *) - 1-tert-butoxycarbonyl-2- (1'-hydroxy-1'-phenyl-methyl) -4-piperidone ethylene ketal (diastereomer A) and (2R *, 1 'S *) - 1-tert.-butoxycarbonyl-2- (1'-hydroxy-1'-phenyl-methyl) -4-piperidonethylene ketal (diastereomer B)

24.3 g (100 mmol) of 1-tert-butoxycarbonyl-4-piperidonethylene ketal and 32.8 ml of tetramethylethylenediamine are dissolved in 100 ml of diethyl ether, cooled to -70 ° and slowly with 87.5 ml (120 mmol) of a solution of secondary butyllithium (1.4 molar solution in Cyclohexane / isopentane) added. The mixture is stirred for 4 hours at -70 °, then 12.72 g (120 mmol) of benzaldehyde are added in one pour and the mixture is allowed to warm to 0 °. Saturated ammonium chloride solution is added to the reaction mixture, which is then extracted with ethyl acetate. The organic phase is separated off, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. Chromatography on silica gel with ethyl acetate as the eluent gives 12.2 g of diastereomer A and 21.6 g of diastereomer B of the title compound. TLC (ethyl acetate / hexane; 1: 1):
Diastereomer A (2R *, 1′R *): R _f = 0.43, mp 133-134 °
Diastereomer B (2R *, 1′S *): R _f = 0.34, mp. 114-116 °

c) 2- (1'-Hydroxy-1'-phenyl-methyl ) -4-piperidone

A suspension of 2.6 g (7.44 mmol) (2R *, 1'R *) - 1-tert-butoxycarbonyl-2- (1'-hydroxy-1'-phenylmethyl) -4-piperidonethylene ketal in 30 ml 6N hydrochloric acid is heated to 60 ° for 1 hour, then cooled, neutralized with sodium carbonate and shaken with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The title compound of mp 124-126 ° is obtained; R _f = 0.26 (methylene chloride / methanol / 25% aqueous ammonia solution, 90: 9.5: 0.5).

d) (2R *, 1'R *) - 1- (3,5-dimethylbenzoyl) -2- (1'-hydroxy-1' -phenylmethyl) -4-piperidone

The crude 2- (1'-hydroxy-1'-phenyl-methyl) -4-piperidone as described under c) above is taken up in a mixture of 20 ml dichloromethane and 20 ml saturated sodium hydrogen carbonate solution, with stirring to 0- 5 ° cooled and 1.5 g (8.9 mmol) of 3,5-dimethylbenzoyl chloride were added dropwise within 1.5 hours. The mixture is stirred for 1 hour, diluted with ethyl acetate, washed successively with 1N HCl and saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness under reduced pressure. The title compound can be purified by chromatography on silica gel with ethyl acetate / hexane (1: 1) as the eluent. TLC (ethyl acetate / hexane; 1: 1): R _f = 0.19, FD-MS: M⁺ = 338.

The following compounds can also be prepared in an analogous manner to that described above under b), c) and d):
(2R *, 1′R *) - 1- (3,5-bistrifluoromethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-chlorophenyl) methyl} -4-piperidone, TLC (ethyl acetate / hexane; 1 : 1): R _f = 0.35; FD-MS: 479.481;
(2R *, 1′R *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (3,4-dichlorophenyl) methyl} -4-piperidone, TLC (ethyl acetate / hexane ; 1: 1): R _f = 0.16, m.p .: 222-223 °;
(2R *, 1′S *) - 1- (3,5-bistrifluoromethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-chlorophenyl) methyl} -4-piperidone
(2R *, 1′R *) - 1- (3,5-bistrifluoromethylbenzoyl) -2- {1′-hydroxy-1 ′ - (3,4-dichlorophenyl) methyl} -4-piperidone
(2R *, 1′R *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-methoxyphenyl) methyl} -4-piperidone
(2R *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-methoxyphenyl) methyll} -4-piperidone
(2R *, 1′R *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (3-methoxyphenyl) methyl} -4-piperidone
(2R *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (3-methoxyphenyl) methyl} -4-piperidone
(2R *, 1′R *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-trifluoromethylphenyl) methyl} -4-piperidone
(2R *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-trifluoromethylphenyl) methyl} -4-piperidone
(2R *, 1′R *) - 1- (3,5-dimethylbenzoyl) -2- (1′-hydroxy-1 ′ - (4-chloro-3-trifluoromethylphenyl) methyl-4-piperidone and
(2R *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-chloro-3-trifluoromethylphenyl) methyl} -4-piperidone.

Example 86: (2R *, 4S *, 1'R *) - 2- (1'-hydroxy-1'-phenyl-methyl) -1- (3,5-dimethylbenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine (Diastereomer A) and (2R *, 4R *, 1′R *) - 1- (3,5-dimethylbenzoyl) -2- (1′-hydroxy-1′-phenyl-methyl) - N- (4-quinolylmethyl) -4- piperidinamine (Diastereomer B)

The title compound can be prepared in a manner analogous to that described in Example 85 starting from 4-quinoline methylamine. It is separated into the diastereomers and purified by column chromatography on silica gel with ethyl acetate and ethyl acetate / methanol (50: 1) as the eluent. TLC (ethyl acetate):
Diastereomer A (2R *, 4S *, 1′R *): R _f = 0.08, FD-MS: M + = 479
Diastereomer B (2R *, 4R *, 1′R *): R _f = 0.01, FD-MS: M + = 479

Example 87 : (2R *, 4S *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- (1′-hydroxy-1′-phenylmethyl) -N- (4-quinolylmethyl) - 4-piperidinamine (diastereomer A) and (2R *, 4R *, 1'S *) - 1- (3,5-dimethyl-benzoyl) -2- (1'-hydroxy-1'-phenyl-methyl) -N - (4-quinolylmethyl) -4-piperidinamine (diastereomer B)

The title compound can be prepared in an analogous manner as described in Example 85 starting from 420 mg (1.24 mmol) (2R *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- (1′-hydroxy-1′- phenyl-methyl) -4-quinolylmethylamine can be produced. she will separated by column chromatography on silica gel with ethyl acetate and dichloromethane / methanol / 35% ammonia solution (95: 4.5: 0.5) as eluent in the diastereomers and purified. TLC (ethyl acetate):
Diastereomer A (2R *, 4S *, 1′S *): R _f = 0.08, FD-MS: M + = 479
Diastereomer B (2R *, 4R *, 1′S *): R _f = 0.01, FD-MS: M + = 479

The starting material can e.g. are manufactured as follows:

a) (2R *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- (1′-hydroxy-1′-phenyl-methyl) -4-piperidone

The title compound is prepared in a manner analogous to that described in Example 1c from 860 mg (2.46 mmol) (2R *, 1′S *) - 1-tert-butoxycarbonyl-2- (1′-hydroxy-1′-phenyl-methyl) -4-piperidonethylene ketal (Example 1b) and purified by column chromatography on silica gel with ethyl acetate / hexane (2: 3) as the eluent. TLC (ethyl acetate / hexane; 1: 1): R _f = 0.24; FD-MS: M + = 337.

Example 88 : (2R *, 4S *, 1′R *) - 2- {1′-Hydroxy-1 ′ - (4-chlorophenyl) methyl} - 1- (3,5-dimethyl-benzoyl) -N- ( 4-quinolylmethyl) -4-piperidinamine (diastereomer A) and (2R *, 4R *, 1′R *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4- chlorphenyl) methyl} -N- (4-quinolylmethyl) -4-piperidinamine (diastereomer B)

The title compound can be prepared in an analogous manner as in Example 1 from 310 mg (0.833 mmol) (2R *, 1'R *) - 1- (3,5-dimethylbenzoyl) -2- {1'-hydroxy-1 '- (4th -chlorophenyl) methyl} -4-piperidone and 145 mg (0.92 mmol) of 4-quinolylmethylamine and separated and purified by column chromatography on silica gel with ethyl acetate / isopropanol (95: 5 - 90:10) as the eluent and purified. TLC (dichloromethane / methanol / 25% Ammonia solution (90: 9.5: 0.5)
Diastereomer A (2R *, 4S *, 1′R *): R _f = 0.47, FD-MS: (M + 1) + = 514
Diastereomer B (2R *, 4R *, 1′R *): R _f = 0.35, FD-MS: M + = 513

The starting material can e.g. are manufactured as follows:

a) (2R *, 1′R *) - 1-tert-butoxycarbonyl-2- {1′-hydroxy-1 ′ - (4-chlorophenyl) methyl} -4-piperidonethylene ketal (diastereomer A) and (2R *, 1′S *) - 1-tert-butoxycarbonyl-2- {1′-hydroxy-1 ′ - (4-chlorophenyl) methyl} -4-piperidonethylene ketal (diastereomer B)

The title compound can be prepared in a manner analogous to that described in Example 1b, starting from 4-chlorobenzaldehyde, separated by column chromatography on silica gel with ethyl acetate / hexane (1: 3) as the eluent and purified, and crystallized from ethyl acetate / hexane. TLC (ethyl acetate / hexane; 1: 1):
Diastereomer A (2R *, 1′R *): R _f = 0.44, mp. 129-130 °
Diastereomer B (2R *, 1′S *): R _f = 0.35, mp 160-161 °

b) (2R *, 1′R *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ (4-chlorophenyl) methyl} -4-piperidone

The title compound can be prepared in an analogous manner to that described in Example 1c and crystallizes from ethyl acetate. Mp 222-225 °; TLC (ethyl acetate / hexane; 1.1): R _f = 0.17

Example 89 : (2R *, 4S *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-chlorophenyl) methyl} -N- (4th -quinolylmethyl) -4-piperidinamine (diastereomer A) and (2R *, 4R *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-chlorophenyl ) -methyl} -N- (4-quinolylmethyl) -4-piperidinamine (diastereomer B)

The title compound can be prepared in an analogous manner as in Example 1 starting from (2R *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-chlorophenyl) methyl} -4-piperidone as the starting material and separated by column chromatography on silica gel with dichloromethane / methanol / 25% ammonia solution (95: 4.5: 0.5) as the eluent and purified. TLC (acetic acid):
Diastereomer A (2R *, 4S *, 1′S *): R _f = 0.24, FD-MS: M + = 514
Diastereomer B (2R *, 4R *, 1′S *): R _f = 0.06, FD-MS: M + = 514

The starting material can be produced, for example, as follows:

a) (2R *, 1′S *) 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-chlorophenyl) methyl} -4-piperidone

The title compound is prepared in a manner analogous to that described in Example 1c, starting from (2R *, 1′S *) - 1-tert-butoxycarbonyl-2- {1′-hydroxy-1 ′ - (4-chlorophenyl) methyl} -4 -piperidonethylene ketal (Example 4a, diastereomer B). Mp 195-197 °; TLC (ethyl acetate / hexane; 1: 1): R _f = 0.26

Example 90 : (2R *, 4S *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (3,4-dichlorophenyl) methyl} -N- (4-Quinolylmethyl) -4-piperidinamine (diastereomer A) and (2R *, 4R *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (3rd , 4-dichlorophenyl) methyl} -N- (4-quinolylmethyl) -4-piperidinamine (diastereomer B)

The title compound is prepared in a manner analogous to that described in Example 1, starting from (2R *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (3,4-dichlorophenyl ) methyl} -4-piperidone and separated by column chromatography on silica gel with dichloromethane / methanol / 25% ammonia solution (93: 6.5: 0.5) as the eluent. TLC (dichloromethane / methanol / 25% ammonia solution; 90: 9.5: 0.5):
Diastereomer A (2R *, 4S *, 1′S *): R _f = 0.38; M.p. 138-140 °
Diastereomer B (2R *, 4R *, 1′S *): R _f = 0.22; M.p. 188-190 °

The starting material can be produced as follows, for example.

a) (2R *, 1′R *) - 1-tert-butoxycarbonyl-2- {1′-hydroxy-1 ′ - (3,4-dichlorophenyl) methyl} -4-piperidonethylene ketal (diastereomer A) and (2R *, 1′S *) - 1-tert-butoxycarbonyl-2- {1′-hydroxy-1 ′ - (3,4-dichlorophenyl) methyl} -4-piperidonethylene ketal (diastereomer B)

The title compound is obtained in an analogous manner to that described in Example 1b, starting from 3,4-dichlorobenzaldehyde instead of benzaldehyde. The diastereomers are separated by column chromatography on silica gel with ethyl acetate / hexane (1: 3) as the eluent and crystallized from ethyl acetate / hexane. TLC (ethyl acetate / hexane; 1: 1):
Diastereomer A (2R *, 1′R *): R _f = 0.57, IR spectrum (methylene chloride): 3700-3300, 1680 cm⁻¹
Diastereomer B (2R *, 1′S *): R _f = 0.48, mp. 160-162 °

b) (2R *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (3,4-dichlorophenyl) methyl} -4-piperidone

The title compound is prepared from (2R *, 1′S *) - 1-tert-butoxycarbonyl-2- {1′-hydroxy-1 ′ - (3,4-dichlorophenyl) methyl} -4 in a manner analogous to that in Example 1c -piperidonethylene ketal prepared and crystallized from ethyl acetate / hexane; Mp 152-152.5 °; TLC (ethyl acetate / hexane; 1: 1), R _f = 0.24

Example 91 (2R *, 4S *) - N-benzyl-1- (3,5-dimethylbenzoyl) -2-benzoyl-4-piperidinamine

wird durch Säulenchromatographie an Silicagel mit Essigsäureethylester als Laufmittel erhalten. TLC (Essigsäureethylester): R_f = 0.17; IR-Spektrum (Methylenchlorid): 1685, 1625, 1500 cm⁻¹.A solution of 30 mg (2R *, 4R *, 1′R *) - N-benzyl-N-trifluoroacetyl-1- (3,5-dimethylbenzoyl) - 2-benzoyl-4-piperidinamine in 5 ml of methanol and 1 ml 5N sodium hydroxide solution is heated to 60 ° for 10 minutes. The mixture is allowed to cool to room temperature, diluted with 10% aqueous sodium hydrogen carbonate solution and shaken twice with dichloromethane. The organic phases are combined, dried over sodium sulfate and evaporated to dryness under reduced pressure. The title compound of the formula

is obtained by column chromatography on silica gel with ethyl acetate as the eluent. TLC (ethyl acetate): R _f = 0.17; IR spectrum (methylene chloride): 1685, 1625, 1500 cm⁻¹.

The starting material can be obtained, for example, as follows:

a) (2R *, 4R *, 1′R *) - N-benzyl-N-trifluoroacetyl-1- (3,5-dimethylbenzoyl) -2-benzoyl-4-piperidinamine

A solution of 80 mg (0.19 mmol) (2R *, 4R *, 1'R *) - N-benzyl-1- (3,5-dimethylbenzoyl) -2- (1'-hydroxy-1'-phenyl-methyl ) -4-piperidinamine (Example 1, diastereomer B) in 1 ml of pyridine is mixed with 0.167 ml of trifluoroacetic anhydride at 0 ° and for 2 hours 0 ° stirred. The reaction mixture is diluted with diethyl ether and water and separated into the phases. The organic phase is washed with 4N hydrochloric acid and saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude product is heated to 55 ° in order to remove trifluoroacetylated by-products in 3 ml of ethanol and 0.5 ml of triethylamine and again evaporated under reduced pressure. The residue is taken up in 3 ml of dichloromethane containing 3 Å molecular sieve and 5 mg of tetrapropylammonium perruthenate and 100 mg of morpholine N-oxide are added. The mixture is stirred for 16 hours, filtered, diluted with dichloromethane, washed successively with sodium hydrogen sulfate solution, saturated sodium chloride solution and 5% copper sulfate solution, dried over sodium sulfate, evaporated under reduced pressure and crystallized from diethyl ether / hexane; M.p. 138-139 °; TLC (ethyl acetate / hexane; 1: 1): R _f = 0.71.

Example 92 : (2R *, 4S *) - 2- (4-chlorobenzyl) -1- (3,5-dimethylbenzoyl) -N- (4-quinolinylmethyl) -4-piperidinamine

in Form weisser Kristalle; Smp. 148-9°; MS: M+ 497.A mixture of 550 mg (1.54 mmol) (2R *, 4S *) - 2- (4-chlorobenzyl) -1- (3,5-dimethylbenzoyl) -4-piperidinamine and 242 mg (1.54 mmol) 4-quinolinecarboxaldehyde is added in 30 ml of toluene dissolved and evaporated to dryness under reduced pressure. This is repeated two more times. The residue is taken up in 10 ml of ethanol, 70 mg (1.85 mmol) of sodium boranate are added and the mixture is stirred at 25 ° for 3 hours. The mixture is acidified with 1N hydrochloric acid and left to stir for 1 hour. The reaction mixture is poured into saturated aqueous sodium carbonate solution and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude product is recrystallized twice from ethyl acetate and gives the title compound of the formula

in the form of white crystals; Mp 148-9 °; MS: M + 497.

The starting materials can be produced, for example, as follows:

a) N-5- (4-Chlorophenyl) pent-1-en-4-yl-3,5-dimethylbenzamide

A solution of 5.0 g (25.6 mmol) of N- [1- (4-chlorophenyl) pent-4-en-2-yl] amine and 5.33 ml (38.4 mmol) of triethylamine in 100 ml of dichloromethane was stirred at 0 ° within 4.3 g (25.6 mmol) of 3,5-dimethylbenzoyl chloride were added over a period of 2 hours. The reaction mixture is stirred for a further 1 hour, 1N hydrochloric acid is added and the mixture is extracted with dichloromethane. The organic phase is washed neutral with saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The crude product is crystallized from ethyl acetate / hexane and gives 7.36 g (88%) of white crystals; M.p. 116-118 °; TLC (hexane / ethyl acetate, 3: 1): R _f = 0.37

b) N- {5- (4-chlorophenyl) pent-1-en-4-yl} -N-ethoxymethyl-3,5-dimethylbenzamide

To a vigorously stirred solution of 5.5 g (16.8 mmol) of N- {5- (4-chlorophenyl) pent-1-en-4-yl} -3,5-dimethylbenzamide and 100 mg of benzyltributylammonium chloride in 15 ml of 50% aqueous solution Sodium hydroxide solution and 15 ml dichloromethane are added at 0-5 ° in 2.36 ml (25.2 mmol) chloromethyl ethyl ether in small portions. The organic phase is taken up in dichloromethane and water, the organic phase is separated off, dried over sodium sulfate and evaporated to dryness under reduced pressure. The oily residue is purified chromatographically on silica gel with ethyl acetate / hexane (1: 4) as the eluent; TLC (ethyl acetate / hexane; 1: 3): R _f = 0.50;
1 H-NMR (300 MHz, CDCl₃): mixture of rotamers, δ = 7.31 -7.18 (m, 4H), 7.04-6.85 (m, 2.6H), 6.42 (br. S, 0.4H), 5.92-5.60 (m , 1H), 5.20-5.02 (m, 2H), 4.54-4.24 (m, 2H), 3.96-3.67 (m, 1H), 3.25-2.40 (m, 6H), 2.28 (s, ca 5H), 2.24 ( s, ca 1H), 1.34-1.21 (m, ca 0.5H), 1.08 (t, J = 7, ca 2.5 H).

c) (2R *, 4S *) - 2- (4-chlorobenzyl) -1- (3,5-dimethylbenzoyl) -N-acetyl-4-piperidinamine

0.61 ml of tin tetrachloride and 0.24 ml acetic anhydride. The reaction mixture is stirred for 2 hours at -20 ° and 1 hour at 25 °, poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is separated off, dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude title compound (orange oil) is combined by chromatography on silica gel with dichloromethane / methanol / 25% ammonia solution (95: 5: 0.1) as the eluent. TLC (dichloromethane / methanol / 25% ammonia solution; 90: 10: 0.1): R _f = 0.45; FD-MS: M + = 398

d) (2R *, 4S *) - 2- (4-chlorobenzyl) -1- (3,5-dimethylbenzoyl) -4-piperidinamine

A suspension of 730 mg (1.83 mmol) (2R *, 4S *) - 2- (4-chlorobenzyl) -1- (3,5-dimethylbenzoyl) -N-acetyl-4-piperidinamine in 6N hydrochloric acid is changed to 100 for 16 hours ° heated, whereby the starting material goes into solution. The reaction mixture is made basic with 10% aqueous sodium carbonate solution and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude title compound is purified by chromatography on silica gel with dichloromethane / methanol / 25% ammonia solution (90: 10: 0.1) as the eluent and is obtained as an almost colorless resin. TLC (dichloromethane / methanol / 25% ammonia solution; 90: 10: 0.1): R _f = 0.26; FD-MS: (M + 1) + = 357

Example 93: (2R *, 4S *) - 2- (3,4-dichlorobenzyl) -1- (3,5-dimethylbenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine

kann in analoger Weise wie in Beispiel 8 ausgehend von (2R*,4S*)-2-(3,4-Dichlorbenzyl)-1-(3,5-dimethylbenzoyl)-4-piperidinamin als Ausgangsstoff hergestellt werden: Smp. 121-124°; TLC (Dichlormethan/Methanol/25 %-ige Ammoniaklösung; 90:9.5:0.5): R_f = 0.30; FD-MS: M+ = 531/533The title compound of the formula

can be prepared in an analogous manner as in Example 8 starting from (2R *, 4S *) - 2- (3,4-dichlorobenzyl) -1- (3,5-dimethylbenzoyl) -4-piperidinamine as starting material: mp 121- 124 °; TLC (dichloromethane / methanol / 25% ammonia solution; 90: 9.5: 0.5): R _f = 0.30; FD-MS: M + = 531/533

The starting material can be produced as follows:

a) N- {5- (3,4-Dichlorophenyl) pent-1-ene-4-yl} -3,5-dimethylbenzamide

The title compound is obtained in 93% yield in an analogous manner to that described in Example 8a; Mp 155-157 °; IR spectrum (KBr): 3230, 1625, 1595 cm -1; TLC (hexane / ethyl acetate; 2: 1): R _f = 0.46

b) N- {5- (3,4-dichlorophenyl) pent-1-ene-4-yl} -N-ethoxymethyl-3,5-dimethylbenzamide

The title compound is obtained in a manner analogous to that described in Example 8b; IR spectrum (film): 1640, 1600 cm⁻¹; TLC (hexane / ethyl acetate; 2: 1): R _f = 0.58

c) (2R *, 4S *) - N-acetyl-2- (3,4-dichlorobenzyl) -1- (3,5-dimethylbenzoyl) -4-piperidinamine

The title compound is obtained in a manner analogous to that described in Example 8c; IR spectrum (KBr): 3260, 1655, 1605, 1595, 1540 cm⁻¹ (KBr); TLC (dichloromethane / methanol; 10: 1); R _f = 0.32

d) (2R *, 4S *) - 2- (3,4-dichlorobenzyl) -1- (3,5-dimethylbenzoyl) -4-piperidinamine

The title compound is obtained in a manner analogous to that described in Example 8d; TLC (Dichloromethane / methanol / 25% ammonia solution; 300: 25: 3): R _f = 0.46

Example 94 : (2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2-phenyl-N- (4-quinolylmethyl) -4-piperidinamine

wird durch Säulenchromatographie an Silicagel mit Dichlormethan/Isopropanol (9:1) als Laufmittel isoliert;
TLC (Dichlormethan/Isopropanol; 9:1): R_f = 0.51; FD-MS: M+ = 449A suspension of 211 mg (0.60 mmol) (2R *, 4S *) - N-acetyl-1- (3,5-dimethylbenzoyl) -2-phenyl-4-piperidinamine in 8 ml of 6N hydrochloric acid is made up to 100 under inert gas for 16 hours ° heated, whereby the starting material dissolves completely. The mixture is allowed to cool to room temperature, neutralized with sodium carbonate solution and extracted with ethyl acetate. Column chromatography on silica gel with dichloromethane / methanol (95: 5 to 90:10) as the eluent gives 135 mg of amine, which is further reacted without further purification with 60 mg (0.38 mmol) of quinoline-4-carboxaldehyde in toluene with azeotropic water removal. After removing the solvent, an oil remains. This is taken up in ethanol and 14 mg (0.38 mmol) of sodium borohydride are added at 0 °. After 1.5 hours, the reaction mixture is treated with 1N hydrochloric acid, stirred for 1 hour at 25 ° and finally neutralized with 10% aqueous sodium carbonate solution. It is shaken out with ethyl acetate, the organic phase is separated off, dried over sodium sulfate and evaporated to dryness under reduced pressure. The title compound of the formula

is isolated by column chromatography on silica gel with dichloromethane / isopropanol (9: 1) as the eluent;
TLC (dichloromethane / isopropanol; 9: 1): R _f = 0.51; FD-MS: M + = 449

The starting material can be produced as follows:

a) (2R *, 4S *) - N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidinamine

A solution of 2.03 g (9.90 mmol) of N-but-3-en-1-yl-O-benzylcarboxamide and 1.14 g (10.7 mmol) of benzaldehyde in 1 ml (810.6 mmol) of acetic anhydride and 20 ml of acetonitrile are added at -20 ° 1.41 ml (12.0 mmol) of tin tetrachloride were added. The mixture is kept at -20 for 16 hours, then treated with 10% aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude title compound is crystallized from ethyl acetate / hexane; M.p. 139-140 °; CI-MS: (M + H) + = 353, (M + NH₄) + = 370.

b) (2R *, 4S *) - N-acetyl-1- (3,5-dimethylbenzoyl) -2-phenyl-4-piperidinamine

A solution of 496 mg (1.41 mmol) (2R *, 4S *) - N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidinamine in 30 ml ethanol and 8 ml 1N hydrochloric acid is mixed with 50 mg 10% Pd / C catalyst added and stirred under a hydrogen atmosphere until no more hydrogen is absorbed. The catalyst is filtered off over diatomaceous earth and the filtrate is evaporated to dryness under reduced pressure. The residue is taken up in 5 ml of dichloromethane and 5 ml of 10% aqueous sodium hydrogen carbonate solution, and 285 mg (1.69 mmol) of 3,5-dimethylbenzoyl chloride are slowly added with stirring at 0 ° within 1 hour. The reaction mixture is extracted with dichloromethane. The organic phase is separated off, dried over sodium sulfate and evaporated to dryness under reduced pressure. The title compound crystallizes from ethyl acetate, mp. 201-203 °; CI-MS: (M + H) + = 351.

Example 95: (2R *, 4S *) - 1- (3,5-dichlorobenzoyl) -2-phenyl-N- (4-quinoline methyl) -4-piperidinamine

kann in analoger Weise wie in Beispiel 10 beschrieben erhalten werden; TLC (Dichlormethan/Methanol/25 %-ige Ammoniaklösung; 90:9.5:0:5): R_f = 0.46; FD-MS: M+ = 489.The title compound of the formula

can be obtained in a manner analogous to that described in Example 10; TLC (dichloromethane / methanol / 25% ammonia solution; 90: 9.5: 0: 5): R _f = 0.46; FD-MS: M + = 489.

The starting material can be produced as follows:

a) (2R *, 4S *) - N-acetyl-1- (3,5-dichlorobenzoyl) -2-phenyl-4-piperidinamine

The title compound will be obtained starting from 3,5-dichlorobenzoyl chloride in an analogous manner as in Example 10b; M.p. 161-163 °; TLC (dichloromethane / methanol / 25% their ammonia solution; 90: 9.5: 0.5): R _f = 0.55.

Example 96: (2R *, 4S *) - 1- (1-naphthoyl) -2-phenyl-N- (4-quinolylmethyl) -4-piperidinamine

wird in analoger Beispiel wie in Beispiel 11 beschrieben erhalten; TLC (Dichlormethan/Methanol/25 %-ige Ammoniaklösung, 90:9.5:0.5): R_f = 0.41; FD-MS: M+ = 471The title compound of the formula

is obtained in a similar example as described in Example 11; TLC (dichloromethane / methanol / 25% ammonia solution, 90: 9.5: 0.5): R _f = 0.41; FD-MS: M + = 471

The starting material is obtained as follows:

a) (2R *, 4S *) - N-acetyl-1- (1-naphthoyl) -2-phenyl-4-piperidinamine

The title compound is obtained in a manner analogous to that described in Example 10b; TLC (dichloromethane / methanol / 25% ammonia solution, 90: 9.5: 0.5): R _f = 0.42.

Example 97: (2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (1-naphthyl) -N- (4-quinolylmethyl) -4-piperidinamine

wird in analoger Weise wie in Beispiel 10 beschrieben erhalten; TLC (Dichlormethan/Methanol/25 %-ige Ammoniaklösung, 90:9.5:0.5): R_f = 0.50 FD-MS: M+ = 499The title compound of the formula

is obtained in an analogous manner as described in Example 10; TLC (dichloromethane / methanol / 25% ammonia solution, 90: 9.5: 0.5): R _f = 0.50 FD-MS: M + = 499

The starting material is obtained as follows:

a) (2R *, 4S *) - N-acetyl-1-benzyloxycarbonyl-2- (1-naphthyl) -4-piperidinamine

The title compound is obtained in a manner analogous to that described in Example 10a, starting from naphthalene-1-carboxaldehyde instead of benzaldehyde; (Dichloromethane / methanol / 25% ammonia solution, 90: 9.5: 0.5): R _f = 0.31 FD-MS: M + = 402.

b) (2R *, 4S *) - (N) -acetyl-1- (3,5-dimethylbenzoyl) -2- (1-naphthyl) -4-piperidinamine

The title compound is obtained in a manner analogous to that described in Example 10b; TLC (dichloromethane / methanol / 25% ammonia solution, 90: 9.5: 0.5): R _f = 0.26 FD-MS: M + = 400.

Example 98:

The following compounds can also be prepared in an analogous manner to that described in Examples 85 to 97:
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (2-naphthyl) -N- (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (4-methoxyphenylmethyl) -N- (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (3-methoxyphenylmethyl) -N- (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (4-nitrobenzyl) -N- (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (4-trifluoromethylphenylmethyl) -N- (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (2,4-dichlorophenylmethyl) -N- (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (2-phenylethyl) -N- (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (2-phenylethenyl) -N- (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2-benzoyl-N- (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (4-chlorobenzoyl) -N- (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (2-naphthyl) -N- (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (4-methoxybenzyl) -N- (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (3-methoxybenzyl) - (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (4-nitrobenzyl) - (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (4-trifluoromethylbenzyl) - (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (2,4-dichlorobenzyl) - (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (2-phenylethyl) - (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (2-phenylethenyl) -N- (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (benzoylmethyl) -N- (4-quinolinylmethyl) -4-piperidinamine;
(2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (4-chlorobenzoylmethyl) -N- (4-quinolinylmethyl) -4-piperidinamine.

Example 99 :

Tablets containing 50 mg each of (2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-phenethyl) -4-piperidinamine or a salt, e.g. the hydrochloride, which can be produced as follows:

Composition (10000 tablets)

Active ingredient

500.0 g

Lactose

500.0 g

Potato starch

352.0 g

gelatin

8.0 g

Talk

60.0 g

Magnesium stearate

10.0 g

Silicon dioxide (highly disperse)

20.0 g

Ethanol

q.s.

The active ingredient is mixed with the lactose and 292 g of potato starch, the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve. After drying, the rest of the potato starch, the magnesium stearate, the talc and the silicon dioxide are mixed in and the mixture is pressed into tablets each having a weight of 145.0 mg and an active substance content of 50.0 mg, which, if desired, are provided with partial notches for finer adjustment of the dosage can.

Example 100 :

Coated tablets containing 100 mg each of (2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-phenethyl) -4-piperidinamine or a salt, e.g. the hydrochloride, which can be produced as follows:

Composition (for 1000 coated tablets)

Active ingredient

100.0 g

Lactose

100.0 g

Cornstarch

70.0 g

Talk

8.5 g

Calcium stearate

1.5 g

Hydroxypropylmethyl cellulose

2.36 g

shellac

0.64 g

water

q.s.

Methylene chloride

q.s.

The active ingredient, the lactose and 40 g of the corn starch are mixed and moistened and granulated with a paste made from 15 g of corn starch and water (with heating). The granules are dried, the rest of the corn starch, the talc and the calcium stearate are added and mixed with the granules. The mixture is pressed into tablets (weight: 280 mg) and these are coated with a solution of hydroxypropylmethylcellulose and shellac in methylene chloride; Final weight of the Lacquer tablet: 283 mg

Example 101 :

Gelatin capsules containing 100 mg of active ingredient, e.g. (2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-phenethyl) -4-piperidinamine or a salt, e.g. the hydrochloride, thereof, can e.g. are manufactured as follows:

Composition (for 1000 capsules)

Active ingredient

100.0 g

Lactose

250.0 g

microcrystalline cellulose

30.0 g

Sodium lauryl sulfate

2.0 g

Magnesium stearate

8.0 g

The sodium lauryl sulfate is sieved through a sieve with a mesh size of 0.2 mm to the lyophilized active ingredient. Both components are mixed intimately. Then the lactose is first sieved through a sieve with a mesh size of 0.6 mm and then the microcrystalline cellulose through a sieve with a mesh size of 0.9 mm. The mixture is then thoroughly mixed again for 10 minutes. Finally, the magnesium stearate is sieved in through a sieve with a mesh size of 0.8 mm. After further mixing for 3 minutes, 390 mg each of the formulation obtained are filled into size 0 gelatin capsules.

Example 102 :

In a manner analogous to that described in Examples 99 to 101 above, it is also possible to prepare pharmaceutical preparations containing another compound of the formula I according to one of the preceding preparation examples.

Claims (123)

A 1-acylpiperidine compound of formula I.

wherein R₁ represents an optionally substituted aralkyl, aryloxyalkyl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl radical or the acyl radical of an optionally substituted by lower alkanoyl or carbamoyl lower amino, R₂ represents cycloalkyl or an optionally substituted aryl or heteroaryl radical, R₃ represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl radical optionally substituted by carboxy or esterified or amidated carboxy, R₄ represents an optionally substituted aryl or optionally partially hydrogenated heteroaryl radical, X₁ Methylene, ethylene, a direct bond, an optionally ketalized carbonyl group or an optionally etherified hydroxymethylene group, X₂ represents alkylene, carbonyl or a direct bond and X₃ carbonyl, oxo lower alkylene, oxo (aza) lower alkylene or represents an optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxy or in higher than the α-position by hydroxy alkylene radical, or a salt thereof. A compound according to claim 1 of formula I, wherein R₁ is a phenyl, diphenyl, naphthyl or fluorenyl-lower alkyl radical which is unsubstituted or substituted in the phenyl part by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and / or trifluoromethyl, an unsubstituted or in the phenyl part by halogen and / or Triazolyl-substituted phenoxy-lower alkyl, a 6-membered monocyclic heteroaryl group or a 6-membered and a 5- or 6-membered ring containing bicyclic azaheteroaryl heteroaryl-lower alkyl group, an unsubstituted or by lower alkyl, lower alkoxy, hydroxyl, di-lower alkylamino, halogeno / halogeno Trifluoromethyl-substituted benzoyl, naphthoyl, fluorenoyl or 3- to 8-membered cycloalkylcarbonyl, an unsubstituted or in the phenyl part by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and / or trifluoromethyl-substituted phenyl or diphenyl-lower alkanoyl group, a bi- or tricyclic azaheteroaryl having 6-membered monocyclic or a 6-membered and one or two 5- or 6-membered ring (s) containing heteroaryl-lower alkanoyl residue, an unsubstituted or in the phenyl part by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and halogen / or trifluoromethyl-substituted phenyl-lower alkoxycarbonyl or N-phenylcarbamoyl radical or the acyl radical of an α-amino acid which is optionally substituted by lower alkanoyl or carbamoyl-lower alkanoyl and which occurs naturally as a peptide building block, R₂ denotes 5- to 7-membered cycloalkyl or an unsubstituted or substituted by aromatic Represents lower alkoxy, halogen and / or trifluoromethyl substituted phenyl, naphthyl or 6-membered monocyclic azaheteroaryl radical, R₃ for hydrogen, lower alkyl, carbamoyl, lower alkanoyl, carboxy-lower alkanoyl or carboxy-lower alkenoyl, lower alkoxycarbonyl-lower alkyl, carb amoyl-lower alkanoyl, N-mono- or N, N-di-lower alkylcarbamoyl-lower alkanoyl, N-cycloalkylcarbamoyl-lower alkanoyl or N-phenylcarbamoyl-lower alkanoyl, R₄ is an unsubstituted or unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl or phenyl or phenyl or pyryl or pyridyl or pyridyl or pyridyl or pyridyl or pyridyl or phenyl or pyridyl or pyrid substituted or unsubstituted phenyl or pyridyl or pyridyl or phenyl or pyridyl or substituted phenyl, or a phenyl or pyrid substituted or unsubstituted phenyl or pyridyl or phenyl or pyridyl or substituted phenyl or phenyl or phenyl or pyridyl or n-substituted phenyl or a phenyl or pyridyl substituted or unsubstituted phenyl or pyridyl or substituted or by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl C-substituted and optionally N-substituted by lower alkanoyl, from an optionally partially hydrogenated 5- or 6-membered mono- or diaza or oxaheteroaryl group and a 6-membered aryl group heteroaryl group, X₁ Methylene, ethylene, a carbonyl group optionally ketalized with a lower alkanol or a lower alkanediol, a hydroxymethylene group optionally etherified with a lower alkanol or a direct bond, X₂ is carbonyl, lower alkylene or a direct bond and X₃ is carbonyl, oxo-lower alkylene, oxo (aza) lower alkylene or an unsubstituted or substituted by phenyl or in 1-, 2- or, if available, 3-position to the N atom by carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N, N-diniederalkylcarbamoyl or hydroxymethyl represents, or a salt thereof. A compound according to claim 1 of formula I, wherein R₁ is unsubstituted or substituted in the phenyl part by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and / or trifluoromethyl phenyl or diphenyl-C₁-C₄-alkyl, unsubstituted or substituted in phenyl by halogen and / or triazolyl Phenoxy-C₁-C₄-alkyl, pyridyl- or quinolinyl-C₁-C₄-alkyl, unsubstituted or substituted by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and / or trifluoromethyl, benzoyl, unsubstituted or by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and / or trifluoromethyl-substituted naphthoyl, unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl pyridylcarbonyl or quinolinylcarbonyl, unsubstituted or substituted by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and / or trifluoromethyl, 5-to 7-membered or unsubstituted cycloalkylcarbonyl Phenyl substituted by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and / or trifluoromethyl, phenyl- or diphenyl-C₁-C₄-alkanoyl, unsubstituted or optionally substituted in the phenyl part by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and / or trifluoromethyl or N-phenylcarbamoyl Group of the formula Ia

represents in the R₅ is hydrogen, unsubstituted or substituted by hydroxy, mercapto, amino, optionally substituted by hydroxy-substituted phenyl, carboxy, carbamoyl or ureido C₁-C₄-alkyl and R₆ C₂-C₇-alkanoyl, R₂ is 5- to 7-membered cycloalkyl or represents an unsubstituted or substituted by aromatically bound C₁-C₄-alkyl, C₁-C₄-alkoxy, halogen and / or trifluoromethyl, phenyl, naphthyl or pyridyl radical, R₃ represents hydrogen, C₁-C₇-alkyl, carbamoyl, C₂-C₇- Alkanoyl, carboxy-C₁-C₄-alkanoyl or carboxy-C₂-C₄-alkenoyl, R₄ is unsubstituted or substituted by C₁-C₄-alkyl, C₁-C₄-alkoxy, halogen and / or trifluoromethyl-substituted phenyl or naphthyl or unsubstituted pyridyl, benzofuranyl, Indolyl, 2,3-dihydroindolyl, benzimidazolyl, quinolyl or 1,2,3,4-tetrahydroquinolinyl means X₁ methylene, hydroxymethylene, C₁-C₄-alkoxymethylene, carbonyl or di-C₁-C₄-alkoxymethylene or one directly e represents bond, X₂ is C₁-C₇-alkylene, carbonyl or a direct bond and X₃ carbonyl, C₁-C₄-alkylene, carboxy-C₁-C₄-alkylene, C₁-C₄-alkoxycarbonyl-C₁-C₄-alkylene, carbamoyl- C₁-C₄ alkylene or hydroxymethyl-C₁-C₄ alkylene, or a salt thereof. A compound according to claim 1 of formula I, wherein R₁ is unsubstituted or substituted by C₁-C₄-alkyl, C₁-C₄-alkoxy, halogen and / or trifluoromethyl benzoyl, naphthoyl or phenyl-C₁-C₄-alkanoyl, unsubstituted pyridylcarbonyl or quinolinylcarbonyl or one Group of the formula Ia

represents in the R₅ hydrogen, unsubstituted or by hydroxy, mercapto, amino, optionally substituted by hydroxyl, phenyl, carboxy, carbamoyl or ureido substituted C₁-C₄-alkyl and R₆ C₂-C₇-alkanoyl means R₂ 5- to 7-membered cycloalkyl or an unsubstituted or substituted by aromatically bound C₁-C₄-alkyl, C₁-C₄-alkoxy, halogen and / or trifluoromethyl-substituted phenyl- Represents naphthyl or pyridyl radical, R₃ represents hydrogen, C₁-C₇-alkyl, carbamoyl, C₂-C₄-alkanoyl, carboxy-C₁-C₄-alkanoyl or carboxy-C₃-C₅-alkenoyl, R₄ is unsubstituted or by C₁-C₄- Alkyl, C₁-C₄-alkoxy, halogen and / or trifluoromethyl substituted phenyl or naphthyl or unsubstituted pyridyl, benzofuranyl, indolyl, benzimidazolyl or quinolyl, X₁ means methylene, hydroxymethylene, C₁-C₄-alkoxymethylene, carbonyl, di-C₁-C₄-alkoxymethylene or represents a direct bond, X₂ represents C₁-C₇alkylene, carbonyl or a direct bond and X₃ carbonyl, C₁-C₄alkylene, carboxy-C₁-C₄alkylene, C₁-C₁alkoxycarbonyl-C₁-C₄alkylene, carbamoyl- C₁-C₄ alkylene, or hydroxymethyl-C₁-C₄-alkylene, or a salt thereof. A compound according to claim 1 of the formula I, in which R₁ is unsubstituted or substituted by C₁-C₄-alkyl, C₁-C₄-alkoxy, halogen of atom number up to and with 35 and / or trifluoromethyl or benzoyl or unsubstituted naphthoyl or phenyl-C₁- C₄-alkanoyl means R₂ is unsubstituted or by C₁-C₄-alkyl, C₁-C₄-alkoxy, halogen of atomic number up to and including 35 and / or trifluoromethyl or mono- or disubstituted phenyl or unsubstituted pyridyl, R₃ is hydrogen, C₁-C₄- Alkyl, carbamoyl or C₂-C₇-alkanoyl, R, is unsubstituted or by C₁-C₄-alkyl, C₁-C₄-alkoxy, halogen of atomic number up to and with 35 and / or trifluoromethyl-mono- or disubstituted phenyl or unsubstituted naphthyl, pyridyl, Benzofuranyl, indolyl, benzimidazolyl or quinolyl means, X₁ represents methylene, hydroxymethylene, carbonyl or a direct bond, X₂ represents a direct bond and X₃ represents C₁-C₄ alkylene lt, or a salt of it. A compound according to claim 1 of formula I, wherein R₁ is unsubstituted or by C₁-C₄-alkyl, C₁-C₄-alkoxy, halogen of atomic number up to and including 35 and / or trifluoromethyl or benzoyl or unsubstituted naphthoyl, R₂ is unsubstituted or by halogen of atomic number up to and with 35 and / or trifluoromethyl represents mono- or disubstituted phenyl, R₃ represents hydrogen, R₄ represents unsubstituted quinolyl, X₁ represents methylene, X₂ represents a direct bond and X₃ represents C₁-C₄ alkylene, or a Salt of it. (2R *, 4S *) - 2-benzyl-1- (2-naphthoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3-trifluoromethylbenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-bis- (trifluoromethyl) benzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (1-naphthoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (2-quinolinylcarbonyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (4-chlorophenylacetyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (benzyloxycarbonyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (2-phenylethyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (2-naphthylacetyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (4-quinolylmethyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (2,4-dichlorobenzyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (2,2-diphenylethyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (phenylcarbamoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (diphenylacetyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (2-pyridylacetyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (4-pyridylacetyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (2,3-diphenylpropionyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1 - ((3S) - (2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indol-3-yl) carbonyl) - N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3-methoxybenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3-N, N-dimethylaminobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (cis, cis-3,5-dimethylcyclohexylcarbonyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-bis- (trifluoromethyl) benzyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2S *, 4R *) - 2-benzyl-1- [2- (5-chloro-1H-1,2,4-triazol-1-yl) phenoxyethyl] -N- (4-quinolylmethyl) -4-piperidinamine or a salt of it. (2R *, 4S *) - 2-benzyl-1 - ((S) -phenylalanyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1 - ((R) -phenylalanyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1 - ((S) -N-acetyl-phenylalanyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1 - ((R) -N-acetyl-phenylalanyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1 - ((S) -N- (4-carboxamido-butyroyl) phenylalanyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1 - ((R) -N- (4-carboxamido-butyroyl) phenylalanyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1-benzoyl-N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3-chlorobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -N- (3-carboxamido-propionyl) -4-piperidinamine or a salt thereof. (2R, 4S) - or (2R, 4R) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2S, 4R) and (2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-phenethyl) -4-piperidinamine or a salt thereof. (2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R, 4S) - or (2R, 4R) -2-benzyl-1- (3,5-dimethylbenzoyl) -N-benzyl-4-piperidinamine or a salt thereof. (2S, 4R) - or (2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N-benzyl-4-piperidinamine or a salt thereof. (2R, 4S) - or (2R, 4R) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-pyridylmethyl) -4-piperidinamine or a salt thereof. (2R, 4S) - or (2R, 4R) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-pyridylmethyl) 4-piperidinamine or a salt thereof. (2S, 4R) - and (2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dimethylbenzoyl) -N-benzyl-N-carbamoyl-4-piperidinamine or a salt thereof. (2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-phenylpropyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-phenylpropyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-methoxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-methoxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-methoxyphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-methoxyphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-methoxyphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-methoxyphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-trifluoromethylbenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-trifluoromethylbenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-trifluoromethylphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-trifluoromethylphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-trifluoromethylphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-trifluoromethylphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-trifluoromethylbenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-trifluoromethylbenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (3-trifluoromethylphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (3-trifluoromethylphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (3-trifluoromethylphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (3-trifluoromethylphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-trifluoromethylbenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-trifluoromethylbenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (4-trifluoromethylphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (4-trifluoromethylphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (4-trifluoromethylphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (4-trifluoromethylphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,3-dimethoxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,3-dimethoxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,3-dimethoxyphenyl) ethyl] -4piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,3-dimethoxyphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,3-dimethoxyphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,3-dimethoxyphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,4-dimethoxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,4-dimethoxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,4-dimethoxyphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,4-dimethoxyphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,4-dimethoxyphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,4-dimethoxyphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,5-dimethoxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,5-dimethoxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,5-dimethoxyphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,5-dimethoxyphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,5-dimethoxyphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,5-dimethoxyphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,6-dimethoxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,6-dimethoxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,6-dimethoxyphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,6-dimethoxyphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,6-dimethoxyphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,6-dimethoxyphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,3-methylenedioxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,3-methylenedioxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,3-methylenedioxyphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,3-methylenedioxyphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,3-methylenedioxyphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,3-methylenedioxyphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,4-methylenedioxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2,4-methylenedioxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,4-methylenedioxyphenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2,4-methylenedioxyphenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,4-methylenedioxyphenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2,4-methylenedioxyphenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-ditrifluoromethylbenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (indol-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (indol-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (quinolin-2-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (quinolin-3-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (2-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [2- (2-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [3- (2-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (3-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [2- (3-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [3- (3-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (4-chlorobenzyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [2- (4-chlorophenyl) ethyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- [3- (4-chlorophenyl) propyl] -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (4-methoxynaphth-1-ylmethyl) -4-piperidinamine;
(2R, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine or
(2S, 4S) -2-benzyl-1- (3,5-dimethoxybenzoyl) -N- (3,4-ethylenedioxybenzyl) -4-piperidinamine or a salt thereof. (2R, 4S) and (2R, 4R) -2-benzyl-1- (3,5-dimethylbenzoyl) -N- (2-phenethyl) -4-piperidinamine or a salt thereof. (2R, 4S) -2-benzyl-1- (3,5-bis (trifluoromethyl) benzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R, 4S) -2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (2,4-dichlorobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (phenylacetyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (2,6-dichlorobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dibromobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (9-fluorenoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3-toluoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3-bromobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dihydroxybenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3-cyanbenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (2-chlorobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (4-chlorobenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (9-fluorenyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -N-methyl-4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -N-cyclohexyl-carbamoyl-4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylmethyl) -N-phenyl-carbamoyl-4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (2-phenylethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-bis- (trifluoromethyl) benzoyl) -N- (2-phenylethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (2-naphthoyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (3,5-dimethylbenzoyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (4-quinolylcarbonyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (3-indolylcarbonyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (2-indolylcarbonyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (5-methoxy-2-indolylcarbonyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (1-naphthoyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (phenylacetyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (2-methoxybenzyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (3- (N-acetyl) indolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (2-benzo [b] furanylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N - [(3-methylbenzo [b] thiophene-2-ylmethyl] -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (5-methoxyindol-3-ylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N- (3-indolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N-phenylcarbamoyl-4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N-diphenylmethyl-4-piperidinamine or a salt thereof. (2R *, 4S *) - 2-benzyl-1- (3,5-dichlorobenzoyl) -N - (3,4-dihydro-2H-1-benzopyran-2-carbonyl) -4-piperidinamine or a salt thereof . (2R *, 4S *) - 2-benzyl-1- (4-methoxybenzoyl) -N- (4-quinolylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *, 1'R *) - N-benzyl-1- (3,5-dimethylbenzoyl) -2- (1'-hydroxy-1'-phenylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *, 1'R *) - 2- (1'-hydroxy-1'-phenyl-methyl) -1- (3,5-dimethylbenzoyl) -N- (4-quinolinylmethyl) -4-piperidinamine or a salt of it. (2R *, 4S *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- (1′-hydroxy-1′-phenylmethyl) -N- (4-quinolinylmethyl) -4-piperidinamine or a salt of it. (2R *, 4S *, 1′R *) - 2- {1′-Hydroxy-1 ′ - (4-chlorophenyl) methyl} -1- (3,5-dimethylbenzoyl) -N- (4-quinolinylmethyl) - 4-piperidinamine or a salt thereof. (2R *, 4S *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-chlorophenyl) methyl} -N- (4-quinolinylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (3,4-dichlorophenyl) methyl} -N- (4- quinolinylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *,) - N-benzyl-1- (3,5-dimethylbenzoyl) -2-benzoyl-4-piperidinamine or a salt thereof. (2R *, 4S *) - 2- (4-chlorobenzyl) -1- (3,5-dimethylbenzoyl) -N- (4-quinolinylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 2- (3,4-dichlorobenzyl) -1- (3,5-dimethylbenzoyl) -N- (4-quinolinylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2-phenyl-N- (4-quinolinylmethyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 1- (3,5-dichlorobenzoyl) -2-phenyl-N- (4-quinoline methyl) -4-piperidinamine or a salt thereof. (2R *, 4S *) - 1- (1-naphthoyl) -2-phenyl-N- (4-quinolinylmethyl) -4-piperidineamine (2R *, 4S *) - 1- (3,5-dimethylbenzoyl) -2- (1-naphthyl) -N- (4-quinolinylmethyl) -4-piperidinamine or a salt thereof. A new 1-acylpiperidone of formula X

wherein R₁ represents an optionally substituted aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl radical or the acyl radical which is optionally substituted by lower alkanoyl or carbamoyl-lower alkanoyl or optionally substituted α-aminoalkyl or R₂ cyclo Heteroarylrest represents, X₁ represents hydroxymethylene and Y₆ and Y₇ together represent oxo, or a salt thereof. A compound according to claim 103 of formula X, wherein R₁ is unsubstituted or by C₁-C₄-alkyl, C₁-C₄-alkoxy, halogen of atomic number up to and including 35 and / or trifluoromethyl or benzoyl or unsubstituted naphthoyl, R₂ is unsubstituted or by halogen of atomic number up to and with 35 and / or trifluoromethyl pheno- or disubstituted phenyl X₁ represents hydroxymethylene, and Y₆ and Y₇ together represent oxo, or a salt thereof. (2R *, 1'R *) - 1- (3,5-dimethylbenzoyl) -2- (1'-hydroxy-1'-phenyl-methyl) -4-piperidone or a salt of it. (2R *, 1′R *) - 1- (3,5-bistrifluoromethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-chlorophenyl) methyl} -4-piperidone or a salt thereof. (2R *, 1′R *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (3,4-dichlorophenyl) methyl} -4-piperidone or a salt thereof. (2R *, 1′S *) - 1- (3,5-bistrifluoromethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-chlorophenyl) methyl} -4-piperidone or a salt thereof. (2R *, 1′R *) - 1- (3,5-bistrifluoromethylbenzoyl) -2- {1′-hydroxy-1 ′ - (3,4-dichlorophenyl) methyl} -4-piperidone or a salt thereof. (2R *, 1′R *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-methoxyphenyl) methyl} -4-piperidone or a salt thereof. (2R *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-methoxyphenyl) methyl} -4-piperidone or a salt thereof. (2R *, 1′R *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (3-methoxyphenyl) methyl} -4-piperidone or a salt thereof. (2R *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- (1′-hydroxy-1 ′ - (3-methoxyphenyl) methyl} -4-piperidone or a salt thereof. (2R *, 1′R *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-trifluoromethylphenyl) methyl} -4-piperidone or a salt thereof. (2R *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-trifluoromethylphenyl) methyl} -4-piperidone or a salt thereof. (2R *, 1′R *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-chloro-3-trifluoromethylphenyl) methyl} -4-piperidone or a salt thereof . (2R *, 1′S *) - 1- (3,5-dimethylbenzoyl) -2- {1′-hydroxy-1 ′ - (4-chloro-3-trifluoromethylphenyl) methyl} -4-piperidone or a salt of it. Compounds according to any one of claims 1 to 117 for use in a method for the therapeutic treatment of the human or animal body. Pharmaceutical preparations, in addition to conventional pharmaceutical auxiliaries, as a pharmaceutical active ingredient containing a compound according to one of Claims 1 and 3 to 49 in free form or in pharmaceutically usable salt form. Pharmaceutical preparations, in addition to conventional pharmaceutical auxiliaries, as a pharmaceutical active ingredient containing a compound according to one of claims 2 and 50 to 118 in free form or in pharmaceutically usable salt form. Process for the preparation of new 1-acylpiperidine compounds of the formula I.

wherein R₁ represents an optionally substituted aralkyl, aryloxyalkyl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl or arylcarbamoyl radical or the acyl radical of an optionally N-alkanoylated α-amino acid, R₂ substituted arylalkyl or an optionally substituted arylalkyl - Or heteroaryl radical, R₃ is hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl radical which is optionally substituted by carboxy or esterified or amidated carboxy, R gegebenenfalls is an optionally substituted aryl or optionally partially hydrogenated heteroaryl radical, X₁ is methylene, ethylene, a direct bond represents an optionally ketalized carbonyl group or an optionally etherified hydroxymethylene group, X₂ represents alkylene, carbonyl or a direct bond and X₃ carbonyl or an optionally esterified or amidated carboxy by hydroxymethyl or higher or higher represents as the α-position substituted by hydroxy alkylene radical, and their salts, characterized in that a) in a compound of formula II

wherein R₂, R₃, R₄, X₁, X₂ and X₃ have the meanings given, the rest introduces R₁ or b) compounds of the formulas III and IV

wherein Y₁ is a group of the formula -N (R₃) -H and Y₂ hydroxy, reactive esterified hydroxy or, if X₃ is carbonyl, etherified hydroxy or Y₁ hydroxy, reactive esterified hydroxy or, if X₂ is carbonyl, etherified hydroxy and Y₂ one Group of the formula -N (R₃) -H represents, where R₂, R₃, R₄, X₁, X₂ and X₃ have the meanings given, or their salts condensed with one another or c) for the preparation of compounds of formula I in which one of the radicals X₂ and X₃ alkylene and the other alkylene, carbonyl or in the case of X₂ a direct bond or in the case of X₃ an alkylene radical optionally substituted by hydroxymethyl or optionally esterified or amidated carboxy represents in a compound of formula V

wherein Z₁ is an α-position to the group -N (R₃) - substituted by oxo or hydroxy alkylene radical and Z₂ alkylene, carbonyl or an alkylene radical optionally substituted by hydroxymethyl or optionally esterified or amidated carboxy means or Z₁ alkylene, carbonyl or a direct bond and Z₂ in the α-position to the group -N (R₃) - is substituted by oxo or hydroxyl substituted alkylene and R₂, R₃, R₄, X₁, X₂ and X₃ have the meanings given, or in a salt thereof the oxo or hydroxy group in the α-position to the group -N (R₃) - reductively replaced by hydrogen or in a compound of formula VI

wherein Z₃ is a radical of the formula -C (R _a ) = C (R _b ) - and Z₄ alkylene, carbonyl or an alkylene radical optionally substituted by hydroxymethyl or optionally esterified or amidated carboxy or Z₃ alkylene, carbonyl or a direct bond and Z₄ one Rest of the formula -C (R _a ) = C (R _b ) -, where R _a and R _b each represent hydrogen or lower alkyl, the rest of the formula -C (R _a ) = C (R _b ) - by reducing the Double bond to the corresponding radical -CH (R _a ) -CH (R _b ) - reduced or d) for the preparation of compounds of the formula I in which X₁ is a carbonyl or hydroxymethylene group, compounds of the formulas VII and VIII

wherein one of the radicals Y₃ and Y₄ formyl or an optionally anhydridized or esterified carboxy group and the other represents a metallic radical and R₂, R₃, R₄, X₂ and X₃ have the meanings given, condensed with one another or e) for the preparation of compounds of formula I, wherein R₃ is hydrogen, from a compound of formula IX

wherein Y₅ is an amino protecting group and R₂, R₄, X₁, X₂ and X₃ the specified Have meanings, or split off the group Y₅ from a salt thereof or f) for the preparation of compounds of the formula I in which X₃ is alkylene, compounds of the formulas X and XI

wherein Y₆ is a group of the formula -N (R₃) -H, Y₇ is hydrogen, Y₈ and Y₉ together are oxo and Z₉ is an alkanylylidene radical corresponding to X₃ or Y₆ and Y₇ are together oxo, Y₈ is a group of the formula -N (R₃) -H, Y₉ Hydrogen and Z₅ represents a radical X₃, condensed with one another under reducing conditions and, if desired, converting a compound obtained into another compound of the formula I, separating an isomer mixture obtainable according to the process into the components and separating off the preferred isomer in each case and / or a free compound obtainable according to the process a salt or a salt obtainable according to the process is converted into the corresponding free compound. Process for the preparation of new 1-acylpiperidones of formula X

wherein R₁ represents an optionally substituted aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl radical or the acyl radical which is optionally substituted by lower alkanoyl or carbamoyl-lower alkanoyl or optionally substituted α-aminoalkyl or R₂ cyclo Heteroarylrest represents, X₁ represents hydroxymethylene and Y₆ and Y₇ together represent oxo, and their salts, characterized in that a compound of formula Xa

condensed with an agent introducing the radical R 1 and, if desired, converting a compound obtained into another compound of the formula I, separating a mixture of isomers which is obtainable according to the process into the components and removing the preferred isomer in each case and / or a free compound which is obtainable according to the process into a salt or a process available salt is converted into the corresponding free compound. Use of a compound according to any one of claims 1 to 118 for the manufacture of a medicament intended for the treatment of diseases in which substance P plays an essential role.